RBCC

Full text data of PML

PML (MYL, PP8675, RNF71, TRIM19) [Confidence: low (only semi-automatic identification from reviews)]
Protein PML (Promyelocytic leukemia protein; RING finger protein 71; Tripartite motif-containing protein 19)

UniProt P29590
ID PML_HUMAN Reviewed; 882 AA.
AC P29590; E9PBR7; P29591; P29592; P29593; Q00755; Q15959; Q59FP9;
read moreAC Q8WUA0; Q96S41; Q9BPW2; Q9BWP7; Q9BZX6; Q9BZX7; Q9BZX8; Q9BZX9;
AC Q9BZY0; Q9BZY2; Q9BZY3;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2008, sequence version 3.
DT 22-JAN-2014, entry version 176.
DE RecName: Full=Protein PML;
DE AltName: Full=Promyelocytic leukemia protein;
DE AltName: Full=RING finger protein 71;
DE AltName: Full=Tripartite motif-containing protein 19;
GN Name=PML; Synonyms=MYL, PP8675, RNF71, TRIM19;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PML-3), AND DISEASE.
RX PubMed=1652369; DOI=10.1016/0092-8674(91)90113-D;
RA de The H., Lavau C., Marchio A., Chomienne C., Degos L., Dejean A.;
RT "The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation
RT in acute promyelocytic leukemia encodes a functionally altered RAR.";
RL Cell 66:675-684(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PML-1; PML-5 AND PML-8),
RP CHROMOSOMAL TRANSLOCATION WITH RARA, DISEASE, AND VARIANT LEU-645.
RX PubMed=1720570; DOI=10.1126/science.1720570;
RA Goddard A.D., Borrow J., Freemont P.S., Solomon E.;
RT "Characterization of a zinc finger gene disrupted by the t(15;17) in
RT acute promyelocytic leukemia.";
RL Science 254:1371-1374(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PML-4).
RX PubMed=1311253;
RA Kastner P., Perez A., Lutz Y., Rochette-Egly C., Gaub M.P., Durand B.,
RA Lanotte M., Berger R., Chambon P.;
RT "Structure, localization and transcriptional properties of two classes
RT of retinoic acid receptor alpha fusion proteins in acute promyelocytic
RT leukemia (APL): structural similarities with a new family of
RT oncoproteins.";
RL EMBO J. 11:629-642(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PML-6).
RX PubMed=1652368; DOI=10.1016/0092-8674(91)90112-C;
RA Kakizuka A., Miller W.H. Jr., Umenono K., Warrell R.P. Jr.,
RA Frankel S.R., Murty V.V., Dmitrovsky E., Evans R.M.;
RT "Chromosomal translocation t(15;17) in human acute promyelocytic
RT leukemia fuses RAR alpha with a novel putative transcription factor,
RT PML.";
RL Cell 66:663-674(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PML-1; PML-2; PML-4; PML-5;
RP PML-6; PML-7; PML-8; PML-12 AND PML-14), AND VARIANT LEU-645.
RX PubMed=11331580; DOI=10.1093/emboj/20.9.2140;
RA Reymond A., Meroni G., Fantozzi A., Merla G., Cairo S., Luzi L.,
RA Riganelli D., Zanaria E., Messali S., Cainarca S., Guffanti A.,
RA Minucci S., Pelicci P.G., Ballabio A.;
RT "The tripartite motif family identifies cell compartments.";
RL EMBO J. 20:2140-2151(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PML-6).
RA Goddard A.D., Solomon E.;
RL Submitted (JAN-1992) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PML-13).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PML-11).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RT "Homo sapiens protein coding cDNA.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human
RT chromosome 15.";
RL Nature 440:671-675(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PML-13).
RC TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 419-466, AND CHROMOSOMAL
RP TRANSLOCATION WITH RARA.
RX PubMed=1312695;
RA Tong J.H., Dong S., Geng J.P., Huang W., Wang Z.Y., Sun G.L.,
RA Chen S.J., Chen Z., Larsen C.-J., Berger R.;
RT "Molecular rearrangements of the MYL gene in acute promyelocytic
RT leukemia (APL, M3) define a breakpoint cluster region as well as some
RT molecular variants.";
RL Oncogene 7:311-316(1992).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 454-503, AND CHROMOSOMAL TRANSLOCATION
RP WITH RARA.
RX PubMed=12691149;
RA Fujita K., Oba R., Harada H., Mori H., Niikura H., Isoyama K.,
RA Omine M.;
RT "Cytogenetics, FISH and RT-PCR analysis of acute promyelocytic
RT leukemia: structure of the fusion point in a case lacking classic
RT t(15;17) translocation.";
RL Leuk. Lymphoma 44:111-115(2003).
RN [13]
RP SUMOYLATION AT LYS-65; LYS-160 AND LYS-490, MUTAGENESIS OF LYS-65;
RP LYS-133; LYS-150; LYS-160 AND LYS-490, SUBCELLULAR LOCATION, AND
RP FUNCTION.
RX PubMed=9756909; DOI=10.1074/jbc.273.41.26675;
RA Kamitani T., Kito K., Nguyen H.P., Wada H., Fukuda-Kamitani T.,
RA Yeh E.T.H.;
RT "Identification of three major sentrinization sites in PML.";
RL J. Biol. Chem. 273:26675-26682(1998).
RN [14]
RP INTERACTION WITH TRIM27.
RX PubMed=9570750;
RA Cao T., Duprez E., Borden K.L., Freemont P.S., Etkin L.D.;
RT "Ret finger protein is a normal component of PML nuclear bodies and
RT interacts directly with PML.";
RL J. Cell Sci. 111:1319-1329(1998).
RN [15]
RP INTERACTION WITH LASSA VIRUS Z PROTEIN.
RX PubMed=9420283;
RA Borden K.L., Campbell-Dwyer E.J., Salvato M.S.;
RT "An arenavirus RING (zinc-binding) protein binds the oncoprotein
RT promyelocyte leukemia protein (PML) and relocates PML nuclear bodies
RT to the cytoplasm.";
RL J. Virol. 72:758-766(1998).
RN [16]
RP FUNCTION, AND INTERACTION WITH RARA; RXRA AND TRIM24.
RX PubMed=10610177; DOI=10.1038/15463;
RA Zhong S., Delva L., Rachez C., Cenciarelli C., Gandini D., Zhang H.,
RA Kalantry S., Freedman L.P., Pandolfi P.P.;
RT "A RA-dependent, tumour-growth suppressive transcription complex is
RT the target of the PML-RARalpha and T18 oncoproteins.";
RL Nat. Genet. 23:287-295(1999).
RN [17]
RP FUNCTION, AND INTERACTION WITH DAXX.
RX PubMed=10684855; DOI=10.1084/jem.191.4.631;
RA Zhong S., Salomoni P., Ronchetti S., Guo A., Ruggero D.,
RA Pandolfi P.P.;
RT "Promyelocytic leukemia protein (PML) and Daxx participate in a novel
RT nuclear pathway for apoptosis.";
RL J. Exp. Med. 191:631-640(2000).
RN [18]
RP INTERACTION WITH DAXX, AND SUBCELLULAR LOCATION.
RX PubMed=10669754; DOI=10.1128/MCB.20.5.1784-1796.2000;
RA Li H., Leo C., Zhu J., Wu X., O'Neil J., Park E.-J., Chen J.D.;
RT "Sequestration and inhibition of Daxx-mediated transcriptional
RT repression by PML.";
RL Mol. Cell. Biol. 20:1784-1796(2000).
RN [19]
RP FUNCTION, INTERACTION WITH TP53, AND SUBCELLULAR LOCATION.
RX PubMed=11025664; DOI=10.1038/35036365;
RA Guo A., Salomoni P., Luo J., Shih A., Zhong S., Gu W., Pandolfi P.P.;
RT "The function of PML in p53-dependent apoptosis.";
RL Nat. Cell Biol. 2:730-736(2000).
RN [20]
RP FUNCTION IN HFV RESTRICTION, INTERACTION WITH HFV BEL1 AND BET, AND
RP SUBCELLULAR LOCATION.
RX PubMed=11432836; DOI=10.1093/emboj/20.13.3495;
RA Regad T., Saib A., Lallemand-Breitenbach V., Pandolfi P.P., de The H.,
RA Chelbi-Alix M.K.;
RT "PML mediates the interferon-induced antiviral state against a complex
RT retrovirus via its association with the viral transactivator.";
RL EMBO J. 20:3495-3505(2001).
RN [21]
RP NOMENCLATURE OF ISOFORMS PML-1 THROUGH PML-7.
RX PubMed=11704850; DOI=10.1038/sj.onc.1204765;
RA Jensen K., Shiels C., Freemont P.S.;
RT "PML protein isoforms and the RBCC/TRIM motif.";
RL Oncogene 20:7223-7233(2001).
RN [22]
RP INTERACTION WITH SIRT1.
RX PubMed=12006491; DOI=10.1093/emboj/21.10.2383;
RA Langley E., Pearson M., Faretta M., Bauer U.-M., Frye R.A.,
RA Minucci S., Pelicci P.G., Kouzarides T.;
RT "Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular
RT senescence.";
RL EMBO J. 21:2383-2396(2002).
RN [23]
RP SUMOYLATION, AND DESUMOYLATION BY SENP2.
RX PubMed=12419228; DOI=10.1016/S1097-2765(02)00699-8;
RA Best J.L., Ganiatsas S., Agarwal S., Changou A., Salomoni P.,
RA Shirihai O., Meluh P.B., Pandolfi P.P., Zon L.I.;
RT "SUMO-1 protease-1 regulates gene transcription through PML.";
RL Mol. Cell 10:843-855(2002).
RN [24]
RP FUNCTION IN DNA REPAIR, PHOSPHORYLATION AT SER-117 BY CHEK2, AND
RP INTERACTION WITH CHEK2.
RX PubMed=12402044; DOI=10.1038/ncb869;
RA Yang S., Kuo C., Bisi J.E., Kim M.K.;
RT "PML-dependent apoptosis after DNA damage is regulated by the
RT checkpoint kinase hCds1/Chk2.";
RL Nat. Cell Biol. 4:865-870(2002).
RN [25]
RP INTERACTION WITH RABIES VIRUS PHOSPHOPROTEINS, SUBCELLULAR LOCATION,
RP AND FUNCTION.
RX PubMed=12439746; DOI=10.1038/sj.onc.1205931;
RA Blondel D., Regad T., Poisson N., Pavie B., Harper F., Pandolfi P.P.,
RA De The H., Chelbi-Alix M.K.;
RT "Rabies virus P and small P products interact directly with PML and
RT reorganize PML nuclear bodies.";
RL Oncogene 21:7957-7970(2002).
RN [26]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CHEK2 AND TP53.
RX PubMed=12810724; DOI=10.1074/jbc.M301264200;
RA Louria-Hayon I., Grossman T., Sionov R.V., Alsheich O., Pandolfi P.P.,
RA Haupt Y.;
RT "The promyelocytic leukemia protein protects p53 from Mdm2-mediated
RT inhibition and degradation.";
RL J. Biol. Chem. 278:33134-33141(2003).
RN [27]
RP INTERACTION WITH TOPBP1.
RX PubMed=12773567; DOI=10.1128/MCB.23.12.4247-4256.2003;
RA Xu Z.-X., Timanova-Atanasova A., Zhao R.-X., Chang K.-S.;
RT "PML colocalizes with and stabilizes the DNA damage response protein
RT TopBP1.";
RL Mol. Cell. Biol. 23:4247-4256(2003).
RN [28]
RP INTERACTION WITH SIAH1, AND DEGRADATION.
RX PubMed=14645235; DOI=10.1074/jbc.M306407200;
RA Fanelli M., Fantozzi A., De Luca P., Caprodossi S., Matsuzawa S.,
RA Lazar M.A., Pelicci P.G., Minucci S.;
RT "The coiled-coil domain is the structural determinant for mammalian
RT homologues of Drosophila Sina-mediated degradation of promyelocytic
RT leukemia protein and other tripartite motif proteins by the
RT proteasome.";
RL J. Biol. Chem. 279:5374-5379(2004).
RN [29]
RP FUNCTION, INTERACTION WITH ELF4, AND SUBCELLULAR LOCATION.
RX PubMed=14976184; DOI=10.1074/jbc.M312439200;
RA Suico M.A., Yoshida H., Seki Y., Uchikawa T., Lu Z., Shuto T.,
RA Matsuzaki K., Nakao M., Li J.-D., Kai H.;
RT "Myeloid Elf-1-like factor, an ETS transcription factor, up-regulates
RT lysozyme transcription in epithelial cells through interaction with
RT promyelocytic leukemia protein.";
RL J. Biol. Chem. 279:19091-19098(2004).
RN [30]
RP INTERACTION WITH ANKRD2.
RX PubMed=15136035; DOI=10.1016/j.jmb.2004.03.071;
RA Kojic S., Medeot E., Guccione E., Krmac H., Zara I., Martinelli V.,
RA Valle G., Faulkner G.;
RT "The Ankrd2 protein, a link between the sarcomere and the nucleus in
RT skeletal muscle.";
RL J. Mol. Biol. 339:313-325(2004).
RN [31]
RP FUNCTION, INTERACTION WITH MDM2 AND RPL11, PHOSPHORYLATION BY ATR IN
RP RESPONSE TO DNA DAMAGE, AND SUBCELLULAR LOCATION.
RX PubMed=15195100; DOI=10.1038/ncb1147;
RA Bernardi R., Scaglioni P.P., Bergmann S., Horn H.F., Vousden K.H.,
RA Pandolfi P.P.;
RT "PML regulates p53 stability by sequestering Mdm2 to the nucleolus.";
RL Nat. Cell Biol. 6:665-672(2004).
RN [32]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH CHFR.
RX PubMed=15467728; DOI=10.1038/nsmb837;
RA Daniels M.J., Marson A., Venkitaraman A.R.;
RT "PML bodies control the nuclear dynamics and function of the CHFR
RT mitotic checkpoint protein.";
RL Nat. Struct. Mol. Biol. 11:1114-1121(2004).
RN [33]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH TGFBR1; TGFBR2;
RP SMAD2; SMAD3 AND ZFYVE9/SARA.
RX PubMed=15356634; DOI=10.1038/nature02783;
RA Lin H.K., Bergmann S., Pandolfi P.P.;
RT "Cytoplasmic PML function in TGF-beta signalling.";
RL Nature 431:205-211(2004).
RN [34]
RP INTERACTION OF PML-RARALPHA ONCOPROTEIN WITH UBE2I, SUBCELLULAR
RP LOCATION, SUMOYLATION, AND MUTAGENESIS OF CYS-88 AND PRO-89.
RX PubMed=15809060; DOI=10.1016/j.bbrc.2005.03.052;
RA Kim Y.E., Kim D.Y., Lee J.M., Kim S.T., Han T.H., Ahn J.H.;
RT "Requirement of the coiled-coil domain of PML-RARalpha oncoprotein for
RT localization, sumoylation, and inhibition of monocyte
RT differentiation.";
RL Biochem. Biophys. Res. Commun. 330:746-754(2005).
RN [35]
RP SUBCELLULAR LOCATION.
RX PubMed=16778193; DOI=10.1158/0008-5472.CAN-05-3792;
RA Condemine W., Takahashi Y., Zhu J., Puvion-Dutilleul F., Guegan S.,
RA Janin A., de The H.;
RT "Characterization of endogenous human promyelocytic leukemia
RT isoforms.";
RL Cancer Res. 66:6192-6198(2006).
RN [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-403; SER-518; SER-527
RP AND SER-530, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-565
RP (ISOFORM PML-5), PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-518;
RP SER-527 AND SER-530 (ISOFORM PML-6), AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [37]
RP FUNCTION.
RX PubMed=17030982; DOI=10.1083/jcb.200604009;
RA Dellaire G., Ching R.W., Ahmed K., Jalali F., Tse K.C., Bristow R.G.,
RA Bazett-Jones D.P.;
RT "Promyelocytic leukemia nuclear bodies behave as DNA damage sensors
RT whose response to DNA double-strand breaks is regulated by NBS1 and
RT the kinases ATM, Chk2, and ATR.";
RL J. Cell Biol. 175:55-66(2006).
RN [38]
RP FUNCTION IN POLIOVIRUS RESTRICTION.
RX PubMed=16912307; DOI=10.1128/JVI.00031-06;
RA Pampin M., Simonin Y., Blondel B., Percherancier Y., Chelbi-Alix M.K.;
RT "Cross talk between PML and p53 during poliovirus infection:
RT implications for antiviral defense.";
RL J. Virol. 80:8582-8592(2006).
RN [39]
RP SUBUNIT, SUMOYLATION, SUMO-BINDING MOTIF, MUTAGENESIS OF CYS-57 AND
RP CYS-60, AND SUBCELLULAR LOCATION.
RX PubMed=17081985; DOI=10.1016/j.molcel.2006.09.013;
RA Shen T.H., Lin H.K., Scaglioni P.P., Yung T.M., Pandolfi P.P.;
RT "The mechanisms of PML-nuclear body formation.";
RL Mol. Cell 24:331-339(2006).
RN [40]
RP INTERACTION WITH PKM, FUNCTION, SUBCELLULAR LOCATION, DOMAIN, AND
RP MUTAGENESIS OF LYS-487 AND LYS-490.
RX PubMed=18298799; DOI=10.1111/j.1365-2443.2008.01165.x;
RA Shimada N., Shinagawa T., Ishii S.;
RT "Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML
RT tumor suppressor protein.";
RL Genes Cells 13:245-254(2008).
RN [41]
RP ACETYLATION AT LYS-487 AND LYS-515, AND MUTAGENESIS OF LYS-487 AND
RP LYS-515.
RX PubMed=18621739; DOI=10.1074/jbc.M802217200;
RA Hayakawa F., Abe A., Kitabayashi I., Pandolfi P.P., Naoe T.;
RT "Acetylation of PML is involved in histone deacetylase inhibitor-
RT mediated apoptosis.";
RL J. Biol. Chem. 283:24420-24425(2008).
RN [42]
RP FUNCTION IN HCMV RESTRICTION.
RX PubMed=17942542; DOI=10.1128/JVI.01685-07;
RA Tavalai N., Papior P., Rechter S., Stamminger T.;
RT "Nuclear domain 10 components promyelocytic leukemia protein and hDaxx
RT independently contribute to an intrinsic antiviral defense against
RT human cytomegalovirus infection.";
RL J. Virol. 82:126-137(2008).
RN [43]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18716620; DOI=10.1038/nature07290;
RA Song M.S., Salmena L., Carracedo A., Egia A., Lo-Coco F.,
RA Teruya-Feldstein J., Pandolfi P.P.;
RT "The deubiquitinylation and localization of PTEN are regulated by a
RT HAUSP-PML network.";
RL Nature 455:813-817(2008).
RN [44]
RP POLYUBIQUITINATION AT LYS-380; LYS-400; LYS-401 AND LYS-476 BY RNF4,
RP PROTEASOMAL DEGRADATION, AND SUMOYLATION.
RX PubMed=18408734; DOI=10.1038/ncb1716;
RA Tatham M.H., Geoffroy M.C., Shen L., Plechanovova A., Hattersley N.,
RA Jaffray E.G., Palvimo J.J., Hay R.T.;
RT "RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for
RT arsenic-induced PML degradation.";
RL Nat. Cell Biol. 10:538-546(2008).
RN [45]
RP FUNCTION, AND INTERACTION WITH SATB1.
RX PubMed=17173041; DOI=10.1038/ncb1516;
RA Kumar P.P., Bischof O., Purbey P.K., Notani D., Urlaub H., Dejean A.,
RA Galande S.;
RT "Functional interaction between PML and SATB1 regulates chromatin-loop
RT architecture and transcription of the MHC class I locus.";
RL Nat. Cell Biol. 9:45-56(2007).
RN [46]
RP FUNCTION IN HHV-1 RESTRICTION, AND SUBCELLULAR LOCATION.
RX PubMed=18509536; DOI=10.1371/journal.pone.0002277;
RA McNally B.A., Trgovcich J., Maul G.G., Liu Y., Zheng P.;
RT "A role for cytoplasmic PML in cellular resistance to viral
RT infection.";
RL PLoS ONE 3:E2277-E2277(2008).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-403; SER-518; SER-527
RP AND SER-530, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [48]
RP FUNCTION IN INFLUENZA A VIRUS RESTRICTION.
RX PubMed=19703418; DOI=10.1016/j.bbrc.2009.08.091;
RA Li W., Wang G., Zhang H., Zhang D., Zeng J., Chen X., Xu Y., Li K.;
RT "Differential suppressive effect of promyelocytic leukemia protein on
RT the replication of different subtypes/strains of influenza A virus.";
RL Biochem. Biophys. Res. Commun. 389:84-89(2009).
RN [49]
RP FUNCTION, AND INTERACTION WITH TERT.
RX PubMed=19567472; DOI=10.1242/jcs.048066;
RA Oh W., Ghim J., Lee E.W., Yang M.R., Kim E.T., Ahn J.H., Song J.;
RT "PML-IV functions as a negative regulator of telomerase by interacting
RT with TERT.";
RL J. Cell Sci. 122:2613-2622(2009).
RN [50]
RP PHOSPHORYLATION AT SER-8 AND SER-38 BY HIPK2, AND INTERACTION WITH
RP HIPK2.
RX PubMed=19015637; DOI=10.1038/onc.2008.420;
RA Gresko E., Ritterhoff S., Sevilla-Perez J., Roscic A., Froebius K.,
RA Kotevic I., Vichalkovski A., Hess D., Hemmings B.A., Schmitz M.L.;
RT "PML tumor suppressor is regulated by HIPK2-mediated phosphorylation
RT in response to DNA damage.";
RL Oncogene 28:698-708(2009).
RN [51]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-530, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [52]
RP FUNCTION IN RABIES VIRUS RESTRICTION.
RX PubMed=20702643; DOI=10.1128/JVI.01286-10;
RA Blondel D., Kheddache S., Lahaye X., Dianoux L., Chelbi-Alix M.K.;
RT "Resistance to rabies virus infection conferred by the PMLIV
RT isoform.";
RL J. Virol. 84:10719-10726(2010).
RN [53]
RP SUMOYLATION, AND UBIQUITINATION.
RX PubMed=20943951; DOI=10.1091/mbc.E10-05-0449;
RA Geoffroy M.C., Jaffray E.G., Walker K.J., Hay R.T.;
RT "Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear
RT bodies.";
RL Mol. Biol. Cell 21:4227-4239(2010).
RN [54]
RP INTERACTION WITH CSNK2A1 AND CSNK2A3.
RX PubMed=20625391; DOI=10.1371/journal.pone.0011418;
RA Hung M.S., Lin Y.C., Mao J.H., Kim I.J., Xu Z., Yang C.T.,
RA Jablons D.M., You L.;
RT "Functional polymorphism of the CK2alpha intronless gene plays
RT oncogenic roles in lung cancer.";
RL PLoS ONE 5:E11418-E11418(2010).
RN [55]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-518 AND SER-527, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [56]
RP INTERACTION WITH UBC9, SUBUNIT, UBIQUITINATION, SUMOYLATION, ARSENIC
RP BINDING, DOMAIN, AND MASS SPECTROMETRY.
RX PubMed=20378816; DOI=10.1126/science.1183424;
RA Zhang X.W., Yan X.J., Zhou Z.R., Yang F.F., Wu Z.Y., Sun H.B.,
RA Liang W.X., Song A.X., Lallemand-Breitenbach V., Jeanne M.,
RA Zhang Q.Y., Yang H.Y., Huang Q.H., Zhou G.B., Tong J.H., Zhang Y.,
RA Wu J.H., Hu H.Y., de The H., Chen S.J., Chen Z.;
RT "Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by
RT directly binding PML.";
RL Science 328:240-243(2010).
RN [57]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [58]
RP FUNCTION, AND INTERACTION WITH WRN.
RX PubMed=21639834; DOI=10.1134/S000629791105004X;
RA Liu J., Song Y., Qian J., Liu B., Dong Y., Tian B., Sun Z.;
RT "Promyelocytic leukemia protein interacts with werner syndrome
RT helicase and regulates double-strand break repair in gamma-
RT irradiation-induced DNA damage responses.";
RL Biochemistry (Mosc.) 76:550-554(2011).
RN [59]
RP REVIEW ON FUNCTION.
RX PubMed=21475307; DOI=10.1038/cdd.2011.31;
RA Pinton P., Giorgi C., Pandolfi P.P.;
RT "The role of PML in the control of apoptotic cell fate: a new key
RT player at ER-mitochondria sites.";
RL Cell Death Differ. 18:1450-1456(2011).
RN [60]
RP REVIEW ON FUNCTION.
RX PubMed=21501958; DOI=10.1016/j.ceb.2011.03.011;
RA Carracedo A., Ito K., Pandolfi P.P.;
RT "The nuclear bodies inside out: PML conquers the cytoplasm.";
RL Curr. Opin. Cell Biol. 23:360-366(2011).
RN [61]
RP PHOSPHORYLATION AT SER-403; SER-505; SER-518 AND SER-527, AND
RP INTERACTION WITH PIN1 AND MAPK1.
RX PubMed=22033920; DOI=10.1074/jbc.M111.289512;
RA Lim J.H., Liu Y., Reineke E., Kao H.Y.;
RT "Mitogen-activated protein kinase extracellular signal-regulated
RT kinase 2 phosphorylates and promotes Pin1 protein-dependent
RT promyelocytic leukemia protein turnover.";
RL J. Biol. Chem. 286:44403-44411(2011).
RN [62]
RP FUNCTION.
RX PubMed=21172801; DOI=10.1242/jcs.075390;
RA Cuchet D., Sykes A., Nicolas A., Orr A., Murray J., Sirma H.,
RA Heeren J., Bartelt A., Everett R.D.;
RT "PML isoforms I and II participate in PML-dependent restriction of
RT HSV-1 replication.";
RL J. Cell Sci. 124:280-291(2011).
RN [63]
RP REVIEW ON FUNCTION IN ANTIVIRAL DEFENSE.
RX PubMed=21198351; DOI=10.1089/jir.2010.0111;
RA Geoffroy M.C., Chelbi-Alix M.K.;
RT "Role of promyelocytic leukemia protein in host antiviral defense.";
RL J. Interferon Cytokine Res. 31:145-158(2011).
RN [64]
RP FUNCTION IN EMCV RESTRICTION, AND INTERACTION WITH EMCV P3D-POL.
RX PubMed=21994459; DOI=10.1128/JVI.05808-11;
RA Maroui M.A., Pampin M., Chelbi-Alix M.K.;
RT "Promyelocytic leukemia isoform IV confers resistance to
RT encephalomyocarditis virus via the sequestration of 3D polymerase in
RT nuclear bodies.";
RL J. Virol. 85:13164-13173(2011).
RN [65]
RP SUMOYLATION, AND DESUMOYLATION BY SENP6.
RX PubMed=21148299; DOI=10.1091/mbc.E10-06-0504;
RA Hattersley N., Shen L., Jaffray E.G., Hay R.T.;
RT "The SUMO protease SENP6 is a direct regulator of PML nuclear
RT bodies.";
RL Mol. Biol. Cell 22:78-90(2011).
RN [66]
RP REVIEW ON FUNCTION.
RX PubMed=21161613; DOI=10.1007/s12035-010-8156-y;
RA Salomoni P., Betts-Henderson J.;
RT "The role of PML in the nervous system.";
RL Mol. Neurobiol. 43:114-123(2011).
RN [67]
RP FUNCTION IN VARICELLA ZOSTER RESTRICTION, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH VZV VP26.
RX PubMed=21304940; DOI=10.1371/journal.ppat.1001266;
RA Reichelt M., Wang L., Sommer M., Perrino J., Nour A.M., Sen N.,
RA Baiker A., Zerboni L., Arvin A.M.;
RT "Entrapment of viral capsids in nuclear PML cages is an intrinsic
RT antiviral host defense against Varicella-Zoster virus.";
RL PLoS Pathog. 7:E1001266-E1001266(2011).
RN [68]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-518; SER-527 AND
RP SER-530, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [69]
RP SUMOYLATION AT LYS-65 AND LYS-160, PHOSPHORYLATION AT SER-565,
RP SUBCELLULAR LOCATION, AND INTERACTION WITH PIAS1; PIAS2 AND CSNK2A1.
RX PubMed=22406621; DOI=10.1158/0008-5472.CAN-11-3159;
RA Rabellino A., Carter B., Konstantinidou G., Wu S.Y., Rimessi A.,
RA Byers L.A., Heymach J.V., Girard L., Chiang C.M., Teruya-Feldstein J.,
RA Scaglioni P.P.;
RT "The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its
RT oncogenic counterpart PML-RARA.";
RL Cancer Res. 72:2275-2284(2012).
RN [70]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH MAGEA2.
RX PubMed=22117195; DOI=10.1038/cdd.2011.173;
RA Peche L.Y., Scolz M., Ladelfa M.F., Monte M., Schneider C.;
RT "MageA2 restrains cellular senescence by targeting the function of
RT PMLIV/p53 axis at the PML-NBs.";
RL Cell Death Differ. 19:926-936(2012).
RN [71]
RP REVIEW ON FUNCTION.
RX PubMed=22237204; DOI=10.1038/cddis.2011.122;
RA Salomoni P., Dvorkina M., Michod D.;
RT "Role of the promyelocytic leukaemia protein in cell death
RT regulation.";
RL Cell Death Dis. 3:E247-E247(2012).
RN [72]
RP FUNCTION, AND INTERACTION WITH TBX2; TBX3; E2F4 AND RBL2.
RX PubMed=22002537; DOI=10.1038/emboj.2011.370;
RA Martin N., Benhamed M., Nacerddine K., Demarque M.D., van Lohuizen M.,
RA Dejean A., Bischof O.;
RT "Physical and functional interaction between PML and TBX2 in the
RT establishment of cellular senescence.";
RL EMBO J. 31:95-109(2012).
RN [73]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PER2, ACETYLATION AT
RP LYS-487, AND DEACETYLATION BY SIRT1.
RX PubMed=22274616; DOI=10.1038/emboj.2012.1;
RA Miki T., Xu Z., Chen-Goodspeed M., Liu M., Van Oort-Jansen A.,
RA Rea M.A., Zhao Z., Lee C.C., Chang K.S.;
RT "PML regulates PER2 nuclear localization and circadian function.";
RL EMBO J. 31:1427-1439(2012).
RN [74]
RP REVIEW ON PTM.
RX PubMed=23316480; DOI=10.3389/fonc.2012.00210;
RA Cheng X., Kao H.Y.;
RT "Post-translational modifications of PML: consequences and
RT implications.";
RL Front. Oncol. 2:210-210(2012).
RN [75]
RP FUNCTION, SUBCELLULAR LOCATION, SUMOYLATION AT LYS-490, AND
RP INTERACTION WITH HDAC7; RANBP2 AND CTNNB1-TCF7L2 COMPLEX.
RX PubMed=22155184; DOI=10.1053/j.gastro.2011.11.041;
RA Satow R., Shitashige M., Jigami T., Fukami K., Honda K.,
RA Kitabayashi I., Yamada T.;
RT "Beta-catenin inhibits promyelocytic leukemia protein tumor suppressor
RT function in colorectal cancer cells.";
RL Gastroenterology 142:572-581(2012).
RN [76]
RP INTERACTION WITH MOMLV IN AND RT, AND SUBCELLULAR LOCATION.
RX PubMed=22685230; DOI=10.1093/jb/mvs063;
RA Okino Y., Inayoshi Y., Kojima Y., Kidani S., Kaneoka H., Honkawa A.,
RA Higuchi H., Nishijima K., Miyake K., Iijima S.;
RT "Moloney murine leukemia virus integrase and reverse transcriptase
RT interact with PML proteins.";
RL J. Biochem. 152:161-169(2012).
RN [77]
RP FUNCTION.
RX PubMed=22589541; DOI=10.1074/jbc.M112.340505;
RA Cheng X., Liu Y., Chu H., Kao H.Y.;
RT "Promyelocytic leukemia protein (PML) regulates endothelial cell
RT network formation and migration in response to tumor necrosis factor
RT alpha (TNFalpha) and interferon alpha (IFNalpha).";
RL J. Biol. Chem. 287:23356-23367(2012).
RN [78]
RP DOMAIN C-TERMINAL.
RX PubMed=22773875; DOI=10.1074/jbc.M112.374769;
RA Geng Y., Monajembashi S., Shao A., Cui D., He W., Chen Z.,
RA Hemmerich P., Tang J.;
RT "Contribution of the C-terminal regions of promyelocytic leukemia
RT protein (PML) isoforms II and V to PML nuclear body formation.";
RL J. Biol. Chem. 287:30729-30742(2012).
RN [79]
RP REVIEW ON UBIQUITINATION.
RX PubMed=22935031; DOI=10.1186/1423-0127-19-81;
RA Chen R.H., Lee Y.R., Yuan W.C.;
RT "The role of PML ubiquitination in human malignancies.";
RL J. Biomed. Sci. 19:81-81(2012).
RN [80]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CIITA.
RX PubMed=23007646; DOI=10.1083/jcb.201112015;
RA Ulbricht T., Alzrigat M., Horch A., Reuter N., von Mikecz A.,
RA Steimle V., Schmitt E., Kraemer O.H., Stamminger T., Hemmerich P.;
RT "PML promotes MHC class II gene expression by stabilizing the class II
RT transactivator.";
RL J. Cell Biol. 199:49-63(2012).
RN [81]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=22886304; DOI=10.1172/JCI62129;
RA Carracedo A., Weiss D., Leliaert A.K., Bhasin M., de Boer V.C.,
RA Laurent G., Adams A.C., Sundvall M., Song S.J., Ito K., Finley L.S.,
RA Egia A., Libermann T., Gerhart-Hines Z., Puigserver P., Haigis M.C.,
RA Maratos-Flier E., Richardson A.L., Schafer Z.T., Pandolfi P.P.;
RT "A metabolic prosurvival role for PML in breast cancer.";
RL J. Clin. Invest. 122:3088-3100(2012).
RN [82]
RP INTERACTION WITH HHV-1 ICP0.
RX PubMed=22875967; DOI=10.1128/JVI.01145-12;
RA Cuchet-Lourenco D., Vanni E., Glass M., Orr A., Everett R.D.;
RT "Herpes simplex virus 1 ubiquitin ligase ICP0 interacts with PML
RT isoform I and induces its SUMO-independent degradation.";
RL J. Virol. 86:11209-11222(2012).
RN [83]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH MDM2 AND MAPK7.
RX PubMed=22869143; DOI=10.1038/onc.2012.332;
RA Yang Q., Liao L., Deng X., Chen R., Gray N.S., Yates J.R. III,
RA Lee J.D.;
RT "BMK1 is involved in the regulation of p53 through disrupting the PML-
RT MDM2 interaction.";
RL Oncogene 32:3156-3164(2013).
RN [84]
RP UBIQUITINATION BY UHRF1.
RX PubMed=22945642; DOI=10.1038/onc.2012.406;
RA Guan D., Factor D., Liu Y., Wang Z., Kao H.Y.;
RT "The epigenetic regulator UHRF1 promotes ubiquitination-mediated
RT degradation of the tumor-suppressor protein promyelocytic leukemia
RT protein.";
RL Oncogene 32:3819-3828(2013).
RN [85]
RP SUMOYLATION, INTERACTION WITH RNF4, AND DOMAIN SIM.
RX PubMed=23028697; DOI=10.1371/journal.pone.0044949;
RA Maroui M.A., Kheddache-Atmane S., El Asmi F., Dianoux L., Aubry M.,
RA Chelbi-Alix M.K.;
RT "Requirement of PML SUMO interacting motif for RNF4- or arsenic
RT trioxide-induced degradation of nuclear PML isoforms.";
RL PLoS ONE 7:E44949-E44949(2012).
RN [86]
RP FUNCTION.
RX PubMed=23219818; DOI=10.1016/j.bbrc.2012.11.108;
RA Kuroki M., Ariumi Y., Hijikata M., Ikeda M., Dansako H., Wakita T.,
RA Shimotohno K., Kato N.;
RT "PML tumor suppressor protein is required for HCV production.";
RL Biochem. Biophys. Res. Commun. 430:592-597(2013).
RN [87]
RP INTERACTION WITH NLRP3.
RX PubMed=23430110; DOI=10.1182/blood-2012-05-432104;
RA Lo Y.H., Huang Y.W., Wu Y.H., Tsai C.S., Lin Y.C., Mo S.T., Kuo W.C.,
RA Chuang Y.T., Jiang S.T., Shih H.M., Lai M.Z.;
RT "Selective inhibition of the NLRP3 inflammasome by targeting to
RT promyelocytic leukemia protein in mouse and human.";
RL Blood 121:3185-3194(2013).
RN [88]
RP FUNCTION, AND INTERACTION WITH HUMAN ADENOVIRUS 2 E1A.
RX PubMed=23135708; DOI=10.1128/JVI.02023-12;
RA Berscheminski J., Groitl P., Dobner T., Wimmer P., Schreiner S.;
RT "The adenoviral oncogene E1A-13S interacts with a specific isoform of
RT the tumor suppressor PML to enhance viral transcription.";
RL J. Virol. 87:965-977(2013).
RN [89]
RP FUNCTION, AND INTERACTION WITH KAT6A.
RX PubMed=23431171; DOI=10.1073/pnas.1300490110;
RA Rokudai S., Laptenko O., Arnal S.M., Taya Y., Kitabayashi I.,
RA Prives C.;
RT "MOZ increases p53 acetylation and premature senescence through its
RT complex formation with PML.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:3895-3900(2013).
RN [90]
RP STRUCTURE BY NMR OF 49-104.
RX PubMed=7729428;
RA Borden K.L.B., Boddy M.N., Lally J., O'Reilly N.J., Martin S.,
RA Howe K., Solomon E., Freemont P.S.;
RT "The solution structure of the RING finger domain from the acute
RT promyelocytic leukaemia proto-oncoprotein PML.";
RL EMBO J. 14:1532-1541(1995).
CC -!- FUNCTION: Functions via its association with PML-nuclear bodies
CC (PML-NBs) in a wide range of important cellular processes,
CC including tumor suppression, transcriptional regulation,
CC apoptosis, senescence, DNA damage response, and viral defense
CC mechanisms. Acts as the scaffold of PML-NBs allowing other
CC proteins to shuttle in and out, a process which is regulated by
CC SUMO-mediated modifications and interactions. Isoform PML-4 has a
CC multifaceted role in the regulation of apoptosis and growth
CC suppression: activates RB1 and inhibits AKT1 via interactions with
CC PP1 and PP2A phosphatases respectively, negatively affects the
CC PI3K pathway by inhibiting MTOR and activating PTEN, and
CC positively regulates p53/TP53 by acting at different levels (by
CC promoting its acetylation and phosphorylation and by inhibiting
CC its MDM2-dependent degradation). Isoform PML-4 also: acts as a
CC transcriptional repressor of TBX2 during cellular senescence and
CC the repression is dependent on a functional RBL2/E2F4 repressor
CC complex, regulates double-strand break repair in gamma-
CC irradiation-induced DNA damage responses via its interaction with
CC WRN, acts as a negative regulator of telomerase by interacting
CC with TERT, and regulates PER2 nuclear localization and circadian
CC function. Isoform PML-6 inhibits specifically the activity of the
CC tetrameric form of PKM. The nuclear isoforms (isoform PML-1,
CC isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in
CC concert with SATB1 are involved in local chromatin-loop remodeling
CC and gene expression regulation at the MHC-I locus. Isoform PML-2
CC is required for efficient IFN-gamma induced MHC II gene
CC transcription via regulation of CIITA. Cytoplasmic PML is involved
CC in the regulation of the TGF-beta signaling pathway. PML also
CC regulates transcription activity of ELF4 and can act as an
CC important mediator for TNF-alpha- and IFN-alpha-mediated
CC inhibition of endothelial cell network formation and migration.
CC -!- FUNCTION: Exhibits antiviral activity against both DNA and RNA
CC viruses. The antiviral activity can involve one or several
CC isoform(s) and can be enhanced by the permanent PML-NB-associated
CC protein DAXX or by the recruitment of p53/TP53 within these
CC structures. Isoform PML-4 restricts varicella zoster virus (VZV)
CC via sequestration of virion capsids in PML-NBs thereby preventing
CC their nuclear egress and inhibiting formation of infectious virus
CC particles. The sumoylated isoform PML-4 restricts rabies virus by
CC inhibiting viral mRNA and protein synthesis. The cytoplasmic
CC isoform PML-14 can restrict herpes simplex virus-1 (HHV-1)
CC replication by sequestering the viral E3 ubiquitin-protein ligase
CC ICP0 in the cytoplasm. Isoform PML-6 shows restriction activity
CC towards human cytomegalovirus (HCMV) and influenza A virus strains
CC PR8(H1N1) and ST364(H3N2). Sumoylated isoform PML-4 and isoform
CC PML-12 show antiviral activity against encephalomyocarditis virus
CC (EMCV) by promoting nuclear sequestration of viral polymerase
CC (P3D-POL) within PML NBs. Isoform PML-3 exhibits antiviral
CC activity against poliovirus by inducing apoptosis in infected
CC cells through the recruitment and the activation of p53/TP53 in
CC the PML-NBs. Isoform PML-3 represses human foamy virus (HFV)
CC transcription by complexing the HFV transactivator, bel1/tas,
CC preventing its binding to viral DNA. PML may positively regulate
CC infectious hepatitis C viral (HCV) production and isoform PML-2
CC may enhance adenovirus transcription.
CC -!- SUBUNIT: Key component of PML bodies. PML bodies are formed by the
CC interaction of PML homodimers (via SUMO-binding motif) with
CC sumoylated PML, leading to the assembly of higher oligomers.
CC Several types of PML bodies have been observed. PML bodies can
CC form hollow spheres that can sequester target proteins inside.
CC Interacts (via SUMO-binding motif) with sumoylated proteins.
CC Interacts (via C-terminus) with p53/TP53. Recruits p53/TP53 and
CC CHEK2 into PML bodies, which promotes p53/TP53 phosphorylation at
CC 'Ser-20' and prevents its proteasomal degradation. Interacts with
CC MDM2, and sequesters MDM2 in the nucleolus, thereby preventing
CC ubiquitination of p53/TP53. Interaction with PML-RARA oncoprotein
CC and certain viral proteins causes disassembly of PML bodies and
CC abolishes the normal PML function. Interacts with HIPK2, TERT,
CC SIRT1, TOPBP1, TRIM27 and TRIM69. Interacts with ELF4 (via C-
CC terminus). Interacts with Lassa virus Z protein and rabies virus
CC phosphoprotein. Interacts with ITPR3. Interacts (in the cytoplasm)
CC with TGFBR1, TGFBR2 and PKM. Interacts (via the coiled-coil domain
CC and when sumoylated) with SATB1. Interacts with UBE2I; the
CC interaction is enhanced by arsenic binding. Interacts (PML-RARA
CC oncoprotein, via the coiled-coil domain) with UBE2I; the
CC interaction is enhanced by arsenic binding and is required for
CC PML-RARA oncoprotein sumoylation and inhibition of RARA
CC transactivational activity. Interacts with RB1, PPP1A, SMAD2,
CC SMAD3, DAXX, RPL11 and MTOR. Interacts with PPARGC1A and KAT2A.
CC Interacts with CSNK2A1 and CSNK2A3. Interacts with ANKRD2; the
CC interaction is direct. Isoform PML-1, isoform PML-2, isoform PML-
CC 3, isoform PML-4, isoform PML-5 and isoform PML-6 interact with
CC RNF4. Isoform PML-1 interacts with NLRP3. Isoform PML-1, isoform
CC PML-2, isoform PML-3, isoform PML-4 and isoform PML-5 interact
CC with MAGEA2, RBL2, PER2 and E2F4. Isoform PML-2 interacts with
CC CIITA. Isoform PML-2, isoform PML-3 and isoform PML-4 interact
CC with TBX2. Isoform PML-4 interacts with RANBP2, HDAC7, KAT6A, WRN,
CC PIN1, TBX3 and phosphorylated MAPK1/ERK2. Isoform PML-4 interacts
CC with the CTNNB1 and TCF7L2/TCF4 complex. Isoform PML-4
CC preferentially interacts with MAPK7/BMK1 although other isoforms
CC (isoform PML-1, isoform PML-2, isoform PML-3 and isoform PML-6)
CC also interact with it. Isoform PML-12 interacts with PIAS1, PIAS2
CC (isoform PIAS2-alpha) and CSNK2A1/CK2. Isoform PML-3 interacts
CC with HFV bel1/tas and bet. Isoform PML-4 interacts with VZV capsid
CC protein VP26/ORF23 capsid protein. Ths sumoylated isoform PML-4
CC interacts with encephalomyocarditis virus (EMCV) RNA-directed RNA
CC polymerase 3D-POL (P3D-POL). Isoform PML-1 interacts with herpes
CC simplex virus-1 (HHV-1) ICP0. Isoform PML-2 interacts with human
CC adenovirus 2 E1A and this interaction stimulates E1A-dependent
CC transcriptional activation. Isoform PML-6 interacts with moloney
CC murine leukemia virus (MoMLV) integrase (IN) and reverse
CC transcriptase (RT).
CC -!- INTERACTION:
CC P03243-1:- (xeno); NbExp=2; IntAct=EBI-303996, EBI-1927377;
CC P04489:- (xeno); NbExp=4; IntAct=EBI-8099068, EBI-6398911;
CC P27958:- (xeno); NbExp=6; IntAct=EBI-295890, EBI-6377335;
CC P68400:CSNK2A1; NbExp=2; IntAct=EBI-295890, EBI-347804;
CC Q9UER7:DAXX; NbExp=6; IntAct=EBI-295890, EBI-77321;
CC P25445:FAS; NbExp=4; IntAct=EBI-295890, EBI-494743;
CC Q9Y2M5:KLHL20; NbExp=9; IntAct=EBI-295890, EBI-714379;
CC Q13164:MAPK7; NbExp=6; IntAct=EBI-295890, EBI-1213983;
CC Q00987:MDM2; NbExp=6; IntAct=EBI-295890, EBI-389668;
CC P25788:PSMA3; NbExp=2; IntAct=EBI-295890, EBI-348380;
CC P63165:SUMO1; NbExp=3; IntAct=EBI-295890, EBI-80140;
CC Q13207:TBX2; NbExp=2; IntAct=EBI-295890, EBI-2853051;
CC O14746:TERT; NbExp=7; IntAct=EBI-304008, EBI-1772203;
CC Q15583:TGIF1; NbExp=3; IntAct=EBI-295890, EBI-714215;
CC P04637:TP53; NbExp=3; IntAct=EBI-295890, EBI-366083;
CC Q05516:ZBTB16; NbExp=7; IntAct=EBI-295890, EBI-711925;
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus, nucleoplasm. Cytoplasm.
CC Nucleus, PML body. Nucleus, nucleolus. Endoplasmic reticulum
CC membrane; Peripheral membrane protein; Cytoplasmic side (By
CC similarity). Early endosome membrane; Peripheral membrane protein;
CC Cytoplasmic side. Note=Isoform PML-1 can shuttle between the
CC nucleus and cytoplasm. Isoform PML-2, isoform PML-3, isoform PML-
CC 4, isoform PML-5 and isoform PML-6 are nuclear isoforms whereas
CC isoform PML-7 and isoform PML-14 lacking the nuclear localization
CC signal are cytoplasmic isoforms. Detected in the nucleolus after
CC DNA damage. Acetylation at Lys-487 is essential for its nuclear
CC localization. Within the nucleus, most of PML is expressed in the
CC diffuse nuclear fraction of the nucleoplasm and only a small
CC fraction is found in the matrix-associated nuclear bodies (PML-
CC NBs). The transfer of PML from the nucleoplasm to PML-NBs depends
CC on its phosphorylation and sumoylation. The B1 box and the RING
CC finger are also required for the localization in PML-NBs. Also
CC found in specific membrane structures termed mitochondria-
CC associated membranes (MAMs) which connect the endoplasmic
CC reticulum (ER) and the mitochondria. Sequestered in the cytoplasm
CC by interaction with rabies virus phosphoprotein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=12;
CC Name=PML-1; Synonyms=PML-I, TRIM19alpha;
CC IsoId=P29590-1; Sequence=Displayed;
CC Name=PML-2; Synonyms=PML-II, TRIM19kappa;
CC IsoId=P29590-8; Sequence=VSP_040595;
CC Name=PML-3; Synonyms=PML-III;
CC IsoId=P29590-9; Sequence=VSP_040596, VSP_040597;
CC Name=PML-4; Synonyms=PML-IV, PML-X, TRIM19zeta;
CC IsoId=P29590-5; Sequence=VSP_005744, VSP_005745;
CC Name=PML-5; Synonyms=PML-2, PML-V, TRIM19beta;
CC IsoId=P29590-2; Sequence=VSP_005739, VSP_005740;
CC Note=Ref.5 (AAG50181) sequence is in conflict in position:
CC 578:P->A. Contains a phosphoserine at position 565;
CC Name=PML-6; Synonyms=PML-3B, PML-VI, TRIM19epsilon;
CC IsoId=P29590-4; Sequence=VSP_005742, VSP_005743;
CC Note=Contains a phosphoserine at position 518. Contains a
CC phosphoserine at position 527. Contains a phosphoserine at
CC position 530;
CC Name=PML-7; Synonyms=PML-VII, TRIM19theta;
CC IsoId=P29590-10; Sequence=VSP_040591, VSP_040594;
CC Note=Ref.5 (AAG50187) sequence is in conflict in position:
CC 419:L->V;
CC Name=PML-8; Synonyms=PML-2G, PML-IIG, TRIM19gamma;
CC IsoId=P29590-3; Sequence=VSP_005741;
CC Note=Non-canonical splice sites. Might alternatively represent a
CC polymorphic variation;
CC Name=PML-11; Synonyms=PML-1A, PML-IA;
CC IsoId=P29590-11; Sequence=VSP_040590;
CC Note=No experimental confirmation available;
CC Name=PML-12; Synonyms=PML-4A, PML-IVA, TRIM19lambda;
CC IsoId=P29590-12; Sequence=VSP_040590, VSP_005744, VSP_005745;
CC Name=PML-13; Synonyms=PML-2A, PML-IIA;
CC IsoId=P29590-13; Sequence=VSP_040590, VSP_040595;
CC Name=PML-14; Synonyms=PML-6B, PML-VIB, TRIM19eta, TRIM19iota;
CC IsoId=P29590-14; Sequence=VSP_040592, VSP_040593;
CC -!- INDUCTION: By interferons alpha, beta and gamma. Up-regulated by
CC IRF3 and p53/TP53.
CC -!- DOMAIN: The coiled-coil domain mediates a strong
CC homo/multidimerization activity essential for core assembly of
CC PML-NBs. Interacts with PKM via its coiled-coil domain
CC (PubMed:18298799).
CC -!- DOMAIN: The B box-type zinc binding domain and the coiled-coil
CC domain mediate its interaction with PIAS1 (PubMed:22406621).
CC -!- DOMAIN: Binds arsenic via the RING-type zinc finger. The RING-type
CC zinc finger is essential for its interaction with HFV bel1/tas
CC (PubMed:11432836).
CC -!- DOMAIN: The unique C-terminal domains of isoform PML-2 and isoform
CC PML-5 play an important role in regulating the localization,
CC assembly dynamics, and functions of PML-NBs (PubMed:22773875).
CC -!- DOMAIN: The Sumo interaction motif (SIM) is required for efficient
CC ubiquitination, recruitment of proteasome components within PML-
CC NBs and PML degradation in response to arsenic trioxide
CC (PubMed:23028697).
CC -!- PTM: Ubiquitinated; mediated by RNF4, UHRF1, UBE3A/E6AP, KLHL20-
CC based E3 ligase complex, SIAH1 or SIAH2 and leading to subsequent
CC proteasomal degradation. Ubiquitination by KLHL20-based E3 ligase
CC complex requires CDK1/2-mediated phosphorylation at Ser-518 which
CC in turn is recognized by prolyl-isopeptidase PIN1 and PIN1-
CC catalyzed isomerization further potentiates PML interaction with
CC KLHL20. 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked
CC polyubiquitination by RNF4 is polysumoylation-dependent.
CC -!- PTM: Sumoylation regulates PML's: stability in response to
CC extracellular or intracellular stimuli, transcription directly and
CC indirectly, through sequestration of or dissociation of the
CC transcription factors from PML-NBs, ability to regulate apoptosis
CC and its anti-viral activities. It is also essential for:
CC maintaining proper PML nuclear bodies (PML-NBs) structure and
CC normal function, recruitment of components of PML-NBs, the
CC turnover and retention of PML in PML-NBs and the integrity of PML-
CC NBs. Undergoes 'Lys-11'-linked sumoylation. Sumoylation on all
CC three sites (Lys-65, Lys-160 and Lys-490) is required for nuclear
CC body formation. Sumoylation on Lys-160 is a prerequisite for
CC sumoylation on Lys-65. Lys-65 and Lys-160 are sumoylated by PISA1
CC and PIAS2. PIAS1-mediated sumoylation of PML promotes its
CC interaction with CSNK2A1/CK2 and phosphorylation at Ser-565 which
CC in turn triggers its ubiquitin-mediated degradation. PIAS1-
CC mediated sumoylation of PML-RARA promotes its ubiquitin-mediated
CC degradation. The PML-RARA fusion protein requires the coiled-coil
CC domain for sumoylation. Sumoylation at Lys-490 by RANBP2 is
CC essential for the proper assembly of PML-NBs. DNA damage triggers
CC its sumoylation while some but not all viral infections can
CC abolish sumoylation. Desumoylated by SENP1, SENP2, SENP3, SENP5
CC and SENP6. Arsenic induces PML and PML-RARA polysumoylation and
CC their subsequent RNF4-dependent ubiquitination and proteasomal
CC degradation, and is used as treatment in acute promyelocytic
CC leukemia (APL). The nuclear isoforms (isoform PML-1, isoform PML-
CC 2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6)
CC show an increased sumoylation in response to arsenic trioxide. The
CC cytoplasmic isoform PML-7 is not sumoylated.
CC -!- PTM: Phosphorylation is a major regulatory mechanism that controls
CC PML protein abundance and the number and size of PML nuclear
CC bodies (PML-NBs). Phosphorylated in response to DNA damage,
CC probably by ATR. HIPK2-mediated phosphorylation at Ser-8, Ser-36
CC and Ser-38 leads to increased accumulation of PML protein and its
CC sumoylation and is required for the maximal pro-apoptotic activity
CC of PML after DNA damage. CHEK2-mediated phosphorylation at Ser-117
CC is important for PML-mediated apopotosis following DNA damage.
CC MAPK1-mediated phosphorylations at Ser-403, Ser-505, Ser-527 and
CC Ser-530 and CDK1/2-mediated phosphorylation at Ser-518 promote
CC PIN1-dependent PML degradation. CK2-mediated phosphorylation at
CC Ser-565 primes PML ubiquitination via an unidentified ubiquitin
CC ligase.
CC -!- PTM: Acetylation at Lys-487 is essential for its nuclear
CC localization. Deacetylated at Lys-487 by SIRT1 and this
CC deacetylation promotes PML control of PER2 nuclear localization.
CC -!- DISEASE: Note=A chromosomal aberration involving PML may be a
CC cause of acute promyelocytic leukemia (APL). Translocation
CC t(15;17)(q21;q21) with RARA. The PML breakpoints (type A and type
CC B) lie on either side of an alternatively spliced exon.
CC -!- SIMILARITY: Contains 2 B box-type zinc fingers.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA60351.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAA60352.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAA60388.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAA60390.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAB62809.1; Type=Miscellaneous discrepancy; Note=Chimeric cDNA;
CC Sequence=BAD92648.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PMLID41.html";
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DR EMBL; S50913; AAB19601.2; -; mRNA.
DR EMBL; M79462; AAA60388.1; ALT_INIT; mRNA.
DR EMBL; M79463; AAA60351.1; ALT_INIT; mRNA.
DR EMBL; M79464; AAA60390.1; ALT_INIT; mRNA.
DR EMBL; X63131; CAA44841.1; -; mRNA.
DR EMBL; M73778; AAA60125.1; -; mRNA.
DR EMBL; M80185; AAA60352.1; ALT_INIT; mRNA.
DR EMBL; AF230401; AAG50180.1; -; mRNA.
DR EMBL; AF230402; AAG50181.1; -; mRNA.
DR EMBL; AF230403; AAG50182.1; -; mRNA.
DR EMBL; AF230405; AAG50184.1; -; mRNA.
DR EMBL; AF230406; AAG50185.1; -; mRNA.
DR EMBL; AF230407; AAG50186.1; -; mRNA.
DR EMBL; AF230408; AAG50187.1; -; mRNA.
DR EMBL; AF230409; AAG50188.1; -; mRNA.
DR EMBL; AF230410; AAG50189.1; -; mRNA.
DR EMBL; AF230411; AAG50190.1; -; mRNA.
DR EMBL; BT009911; AAP88913.1; -; mRNA.
DR EMBL; AB209411; BAD92648.1; ALT_INIT; mRNA.
DR EMBL; AC013486; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC108137; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000080; AAH00080.2; -; mRNA.
DR EMBL; BC020994; AAH20994.1; -; mRNA.
DR EMBL; X64800; CAA46026.1; -; Genomic_DNA.
DR EMBL; AB067754; BAB62809.1; ALT_SEQ; mRNA.
DR PIR; A40044; A40044.
DR PIR; I38054; I38054.
DR PIR; S19244; S19244.
DR PIR; S42516; S42516.
DR PIR; S44381; S44381.
DR RefSeq; NP_002666.1; NM_002675.3.
DR RefSeq; NP_150241.2; NM_033238.2.
DR RefSeq; NP_150242.1; NM_033239.2.
DR RefSeq; NP_150243.2; NM_033240.2.
DR RefSeq; NP_150247.2; NM_033244.3.
DR RefSeq; NP_150249.1; NM_033246.2.
DR RefSeq; NP_150250.2; NM_033247.2.
DR RefSeq; NP_150252.1; NM_033249.2.
DR RefSeq; NP_150253.2; NM_033250.2.
DR RefSeq; XP_005254508.1; XM_005254451.1.
DR RefSeq; XP_005254509.1; XM_005254452.1.
DR RefSeq; XP_005254514.1; XM_005254457.1.
DR RefSeq; XP_005254515.1; XM_005254458.1.
DR RefSeq; XP_005254516.1; XM_005254459.1.
DR RefSeq; XP_005254517.1; XM_005254460.1.
DR UniGene; Hs.526464; -.
DR PDB; 1BOR; NMR; -; A=49-104.
DR PDBsum; 1BOR; -.
DR ProteinModelPortal; P29590; -.
DR SMR; P29590; 49-104.
DR IntAct; P29590; 66.
DR MINT; MINT-158826; -.
DR STRING; 9606.ENSP00000268058; -.
DR PhosphoSite; P29590; -.
DR DMDM; 215274219; -.
DR PaxDb; P29590; -.
DR PRIDE; P29590; -.
DR DNASU; 5371; -.
DR Ensembl; ENST00000268058; ENSP00000268058; ENSG00000140464.
DR Ensembl; ENST00000268059; ENSP00000268059; ENSG00000140464.
DR Ensembl; ENST00000354026; ENSP00000315434; ENSG00000140464.
DR Ensembl; ENST00000359928; ENSP00000353004; ENSG00000140464.
DR Ensembl; ENST00000395132; ENSP00000378564; ENSG00000140464.
DR Ensembl; ENST00000395135; ENSP00000378567; ENSG00000140464.
DR Ensembl; ENST00000435786; ENSP00000395576; ENSG00000140464.
DR Ensembl; ENST00000436891; ENSP00000394642; ENSG00000140464.
DR Ensembl; ENST00000564428; ENSP00000457023; ENSG00000140464.
DR Ensembl; ENST00000565898; ENSP00000455838; ENSG00000140464.
DR Ensembl; ENST00000567543; ENSP00000456277; ENSG00000140464.
DR Ensembl; ENST00000569477; ENSP00000455612; ENSG00000140464.
DR Ensembl; ENST00000569965; ENSP00000456486; ENSG00000140464.
DR GeneID; 5371; -.
DR KEGG; hsa:5371; -.
DR UCSC; uc002awv.3; human.
DR CTD; 5371; -.
DR GeneCards; GC15P074287; -.
DR HGNC; HGNC:9113; PML.
DR HPA; CAB010194; -.
DR HPA; CAB016304; -.
DR HPA; HPA008312; -.
DR MIM; 102578; gene.
DR neXtProt; NX_P29590; -.
DR Orphanet; 520; Acute promyelocytic leukemia.
DR PharmGKB; PA33439; -.
DR eggNOG; NOG326718; -.
DR HOVERGEN; HBG000552; -.
DR InParanoid; P29590; -.
DR KO; K10054; -.
DR OMA; SDAENSC; -.
DR OrthoDB; EOG7M98FM; -.
DR PhylomeDB; P29590; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P29590; -.
DR ChiTaRS; PML; human.
DR EvolutionaryTrace; P29590; -.
DR GeneWiki; Promyelocytic_leukemia_protein; -.
DR GenomeRNAi; 5371; -.
DR NextBio; 20820; -.
DR PMAP-CutDB; P29590; -.
DR PRO; PR:P29590; -.
DR ArrayExpress; P29590; -.
DR Bgee; P29590; -.
DR CleanEx; HS_PML; -.
DR Genevestigator; P29590; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042406; C:extrinsic to endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; IDA:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IDA:UniProtKB.
DR GO; GO:0050897; F:cobalt ion binding; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IDA:UniProtKB.
DR GO; GO:0060444; P:branching involved in mammary gland duct morphogenesis; IEA:Ensembl.
DR GO; GO:0007050; P:cell cycle arrest; IDA:UniProtKB.
DR GO; GO:0045165; P:cell fate commitment; IEA:Ensembl.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0090398; P:cellular senescence; IDA:UniProtKB.
DR GO; GO:0007182; P:common-partner SMAD protein phosphorylation; IEA:Ensembl.
DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; ISS:UniProtKB.
DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; ISS:UniProtKB.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IDA:UniProtKB.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0051457; P:maintenance of protein location in nucleus; IDA:MGI.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0030099; P:myeloid cell differentiation; IEA:Ensembl.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IMP:BHF-UCL.
DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IDA:UniProtKB.
DR GO; GO:2000059; P:negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0051974; P:negative regulation of telomerase activity; IMP:UniProtKB.
DR GO; GO:0032211; P:negative regulation of telomere maintenance via telomerase; IMP:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0032938; P:negative regulation of translation in response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0030578; P:PML body organization; IDA:UniProtKB.
DR GO; GO:0060058; P:positive regulation of apoptotic process involved in mammary gland involution; IDA:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IMP:UniProtKB.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0031065; P:positive regulation of histone deacetylation; IDA:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR GO; GO:0006461; P:protein complex assembly; IDA:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR GO; GO:0006605; P:protein targeting; IDA:UniProtKB.
DR GO; GO:0010522; P:regulation of calcium ion transport into cytosol; ISS:UniProtKB.
DR GO; GO:2000779; P:regulation of double-strand break repair; IMP:UniProtKB.
DR GO; GO:0045343; P:regulation of MHC class I biosynthetic process; IEA:Ensembl.
DR GO; GO:0001932; P:regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0010332; P:response to gamma radiation; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB.
DR GO; GO:0009411; P:response to UV; IEA:Ensembl.
DR GO; GO:0048384; P:retinoic acid receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007184; P:SMAD protein import into nucleus; IEA:Ensembl.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR021978; DUF3583.
DR InterPro; IPR000315; Znf_B-box.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR Pfam; PF12126; DUF3583; 1.
DR Pfam; PF00643; zf-B_box; 1.
DR SMART; SM00336; BBOX; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS50119; ZF_BBOX; 2.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Alternative splicing;
KW Antiviral defense; Apoptosis; Chromosomal rearrangement; Coiled coil;
KW Complete proteome; Cytoplasm; DNA-binding; Endoplasmic reticulum;
KW Endosome; Host-virus interaction; Immunity; Innate immunity;
KW Isopeptide bond; Membrane; Metal-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Proto-oncogene; Reference proteome; Repeat;
KW Transcription; Transcription regulation; Tumor suppressor;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1 882 Protein PML.
FT /FTId=PRO_0000056001.
FT ZN_FING 57 92 RING-type.
FT ZN_FING 124 166 B box-type 1; atypical.
FT ZN_FING 183 236 B box-type 2.
FT REGION 448 555 Interaction with PER2.
FT REGION 476 490 Nuclear localization signal.
FT REGION 556 562 Sumo interaction motif (SIM).
FT COILED 228 253 Potential.
FT COMPBIAS 3 46 Pro-rich.
FT METAL 57 57 Zinc 1.
FT METAL 60 60 Zinc 1.
FT METAL 72 72 Zinc 2.
FT METAL 74 74 Zinc 2.
FT METAL 77 77 Zinc 1.
FT METAL 80 80 Zinc 1.
FT METAL 88 88 Zinc 2.
FT METAL 91 91 Zinc 2.
FT SITE 394 395 Breakpoint for translocation to form PML-
FT RARA oncogene in type A APL.
FT SITE 552 553 Breakpoint for translocation to form PML-
FT RARA oncogene in type B APL.
FT MOD_RES 8 8 Phosphoserine; by HIPK2.
FT MOD_RES 28 28 Phosphothreonine; by MAPK1.
FT MOD_RES 36 36 Phosphoserine; by HIPK2 and MAPK1.
FT MOD_RES 38 38 Phosphoserine; by HIPK2 and MAPK1.
FT MOD_RES 40 40 Phosphoserine; by MAPK1.
FT MOD_RES 42 42 Phosphothreonine.
FT MOD_RES 117 117 Phosphoserine; by CHEK2.
FT MOD_RES 403 403 Phosphoserine; by MAPK1 and MAPK7.
FT MOD_RES 409 409 Phosphothreonine; by MAPK7.
FT MOD_RES 487 487 N6-acetyllysine.
FT MOD_RES 504 504 Phosphoserine (By similarity).
FT MOD_RES 505 505 Phosphoserine; by MAPK1.
FT MOD_RES 515 515 N6-acetyllysine (Probable).
FT MOD_RES 518 518 Phosphoserine; by CDK1 and CDK2.
FT MOD_RES 527 527 Phosphoserine; by MAPK1.
FT MOD_RES 530 530 Phosphoserine; by MAPK1.
FT MOD_RES 535 535 Phosphoserine.
FT MOD_RES 565 565 Phosphoserine; by CK2.
FT CROSSLNK 65 65 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 160 160 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 380 380 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 400 400 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 401 401 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 476 476 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 490 490 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 497 497 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT VAR_SEQ 419 466 Missing (in isoform PML-11, isoform PML-
FT 12 and isoform PML-13).
FT /FTId=VSP_040590.
FT VAR_SEQ 419 435 PEEAERVKAQVQALGLA -> LPPPAHALTGPAQSSTH
FT (in isoform PML-7).
FT /FTId=VSP_040591.
FT VAR_SEQ 419 423 PEEAE -> RNALW (in isoform PML-14).
FT /FTId=VSP_040592.
FT VAR_SEQ 424 882 Missing (in isoform PML-14).
FT /FTId=VSP_040593.
FT VAR_SEQ 436 882 Missing (in isoform PML-7).
FT /FTId=VSP_040594.
FT VAR_SEQ 553 560 EERVVVIS -> GRERNALW (in isoform PML-6).
FT /FTId=VSP_005742.
FT VAR_SEQ 561 882 Missing (in isoform PML-6).
FT /FTId=VSP_005743.
FT VAR_SEQ 571 882 SSRELDDSSSESSDLQLEGPSTLRVLDENLADPQAEDRPLV
FT FFDLKIDNETQKISQLAAVNRESKFRVVIQPEAFFSIYSKA
FT VSLEVGLQHFLSFLSSMRRPILACYKLWGPGLPNFFRALED
FT INRLWEFQEAISGFLAALPLIRERVPGASSFKLKNLAQTYL
FT ARNMSERSAMAAVLAMRDLCRLLEVSPGPQLAQHVYPFSSL
FT QCFASLQPLVQAAVLPRAEARLLALHNVSFMELLSAHRRDR
FT QGGLKKYSRYLSLQTTTLPPAQPAFNLQALGTYFEGLLEGP
FT ALARAEGVSTPLAGRGLAERASQQS -> CMEPMETAEPQS
FT SPAHSSPAHSSPAHSSPVQSLLRAQGASSLPCGTYHPPAWP
FT PHQPAEQAATPDAEPHSEPPDHQERPAVHRGIRYLLYRAQR
FT AIRLRHALRLHPQLHRAPIRTWSPHVVQASTPAITGPLNHP
FT ANAQEHPAQLQRGISPPHRIRGAVRSRSRSLRGSSHLSQWL
FT NNFFALPFSSMASQLDMSSVVGAGESRAQTLGAGVPPGDSV
FT RGSMEASQVQVPLEASPITFPPPCAPERPPISPVPGARQAG
FT L (in isoform PML-2 and isoform PML-13).
FT /FTId=VSP_040595.
FT VAR_SEQ 571 882 SSRELDDSSSESSDLQLEGPSTLRVLDENLADPQAEDRPLV
FT FFDLKIDNETQKISQLAAVNRESKFRVVIQPEAFFSIYSKA
FT VSLEVGLQHFLSFLSSMRRPILACYKLWGPGLPNFFRALED
FT INRLWEFQEAISGFLAALPLIRERVPGASSFKLKNLAQTYL
FT ARNMSERSAMAAVLAMRDLCRLLEVSPGPQLAQHVYPFSSL
FT QCFASLQPLVQAAVLPRAEARLLALHNVSFMELLSAHRRDR
FT QGGLKKYSRYLSLQTTTLPPAQPAFNLQALGTYFEGLLEGP
FT ALARAEGVSTPLAGRGLAERASQQS -> CMEPMETAEPQS
FT SPAHSSPAHSSPVQSLLRAQGASSLPCGTYHPPAWPPHQPA
FT EQAATPDAEPHSEPPDHQERPAVHRGIRYLLYRAQRAIRLR
FT HALRLHPQLHRAPIRTWSPHVVQASTPAITGPLNHPANAQE
FT HPAQLQRGISPPHRIRGAVRSRSRSLRGSSHLSQWLNNFFA
FT LPFSSMASQLDMSSVVGAGEGRAQTLGAVVPPGDSVRGSME
FT ASQVQVPLEASPITFPPPCAPERPPISPVPGARQAGL (in
FT isoform PML-8).
FT /FTId=VSP_005741.
FT VAR_SEQ 571 641 SSRELDDSSSESSDLQLEGPSTLRVLDENLADPQAEDRPLV
FT FFDLKIDNETQKISQLAAVNRESKFRVVIQ -> VSSSPQS
FT EVLYWKVHGAHGDRRATVLASPLLASPLLASPLLASPVSAE
FT STRSLQPALWHIPPPSLASPPAR (in isoform PML-
FT 3).
FT /FTId=VSP_040596.
FT VAR_SEQ 571 611 SSRELDDSSSESSDLQLEGPSTLRVLDENLADPQAEDRPLV
FT -> VSGPEVQPRTPASPHFRSQGAQPQQVTLRLALRLGNFP
FT VRH (in isoform PML-5).
FT /FTId=VSP_005739.
FT VAR_SEQ 612 882 Missing (in isoform PML-5).
FT /FTId=VSP_005740.
FT VAR_SEQ 621 633 TQKISQLAAVNRE -> SGFSWGYPHPFLI (in
FT isoform PML-4 and isoform PML-12).
FT /FTId=VSP_005744.
FT VAR_SEQ 634 882 Missing (in isoform PML-4 and isoform
FT PML-12).
FT /FTId=VSP_005745.
FT VAR_SEQ 642 882 Missing (in isoform PML-3).
FT /FTId=VSP_040597.
FT VARIANT 645 645 F -> L (in dbSNP:rs5742915).
FT /FTId=VAR_052090.
FT MUTAGEN 57 57 C->S: Strongly reduced sumoylation; when
FT associated with S-60.
FT MUTAGEN 60 60 C->S: Strongly reduced sumoylation; when
FT associated with S-57.
FT MUTAGEN 65 65 K->R: Loss of one sumoylation. No effect
FT on nuclear body formation. Loss of 2
FT sumoylations; when associated with R-490
FT with or without R-133 or R-150. No effect
FT on nuclear body formation; when
FT associated with R-490. No sumoylation nor
FT nuclear body formation; when associated
FT with R-160 and R-490.
FT MUTAGEN 68 68 K->R: No effect on sumoylation levels.
FT MUTAGEN 88 88 C->S: No nuclear microspeckle location,
FT no sumoylation and loss of intrinsic
FT transcriptional repressor activity of
FT PML-RARA oncoprotein; when associated
FT with R-89.
FT MUTAGEN 89 89 P->R: No nuclear microspeckle location,
FT no sumoylation and loss of intrinsic
FT transcriptional repressor activity of
FT PML-RARA oncoprotein; when associated
FT with S-88.
FT MUTAGEN 133 133 K->R: Loss of 2 sumoylations; when
FT associated with R-65 and R-490.
FT MUTAGEN 150 150 K->R: Loss of 2 sumoylations; when
FT associated with R-65 and R-490.
FT MUTAGEN 160 160 K->R: Loss of 2 sumoylations; when
FT associated with or without R-65. No
FT sumoylation nor nuclear body formation;
FT when associated with or without R-65 and
FT R-490.
FT MUTAGEN 487 487 K->A: Loss of nuclear localization; when
FT associated with A-490.
FT MUTAGEN 487 487 K->R: Loss of nuclear localization.
FT Reduced acetylation. Further decrease in
FT acetylation; when associated with R-515.
FT MUTAGEN 490 490 K->A: Loss of nuclear localization; when
FT associated with A-487.
FT MUTAGEN 490 490 K->R: Loss of 2 sumoylations; when
FT associated with R-65 with or without R-
FT 133. No effect on nuclear body formation;
FT when associated with R-65. No sumoylation
FT nor nuclear body formation; when
FT associated with R-65 and R-160.
FT MUTAGEN 515 515 K->R: Slightly reduced acetylation.
FT Further decrease in acetylation; when
FT associated with R-487.
FT MUTAGEN 556 559 VVVI->AAAS: Abolishes SUMO1 binding.
FT CONFLICT 224 224 E -> D (in Ref. 7; AAP88913 and 10;
FT AAH00080/AAH20994).
FT CONFLICT 419 419 P -> A (in Ref. 2; AAA60351/AAA60388/
FT AAA60390, 4; AAA60352 and 5; AAG50182/
FT AAG50184/AAG50185).
FT STRAND 58 60
FT STRAND 82 87
FT STRAND 93 96
SQ SEQUENCE 882 AA; 97551 MW; D50968A977E34287 CRC64;
MEPAPARSPR PQQDPARPQE PTMPPPETPS EGRQPSPSPS PTERAPASEE EFQFLRCQQC
QAEAKCPKLL PCLHTLCSGC LEASGMQCPI CQAPWPLGAD TPALDNVFFE SLQRRLSVYR
QIVDAQAVCT RCKESADFWC FECEQLLCAK CFEAHQWFLK HEARPLAELR NQSVREFLDG
TRKTNNIFCS NPNHRTPTLT SIYCRGCSKP LCCSCALLDS SHSELKCDIS AEIQQRQEEL
DAMTQALQEQ DSAFGAVHAQ MHAAVGQLGR ARAETEELIR ERVRQVVAHV RAQERELLEA
VDARYQRDYE EMASRLGRLD AVLQRIRTGS ALVQRMKCYA SDQEVLDMHG FLRQALCRLR
QEEPQSLQAA VRTDGFDEFK VRLQDLSSCI TQGKDAAVSK KASPEAASTP RDPIDVDLPE
EAERVKAQVQ ALGLAEAQPM AVVQSVPGAH PVPVYAFSIK GPSYGEDVSN TTTAQKRKCS
QTQCPRKVIK MESEEGKEAR LARSSPEQPR PSTSKAVSPP HLDGPPSPRS PVIGSEVFLP
NSNHVASGAG EAEERVVVIS SSEDSDAENS SSRELDDSSS ESSDLQLEGP STLRVLDENL
ADPQAEDRPL VFFDLKIDNE TQKISQLAAV NRESKFRVVI QPEAFFSIYS KAVSLEVGLQ
HFLSFLSSMR RPILACYKLW GPGLPNFFRA LEDINRLWEF QEAISGFLAA LPLIRERVPG
ASSFKLKNLA QTYLARNMSE RSAMAAVLAM RDLCRLLEVS PGPQLAQHVY PFSSLQCFAS
LQPLVQAAVL PRAEARLLAL HNVSFMELLS AHRRDRQGGL KKYSRYLSLQ TTTLPPAQPA
FNLQALGTYF EGLLEGPALA RAEGVSTPLA GRGLAERASQ QS
//

MIM 102578
*RECORD*
*FIELD* NO
102578
*FIELD* TI
*102578 ACUTE PROMYELOCYTIC LEUKEMIA, INDUCER OF; PML
;;MYL
PML/RARA FUSION GENE, INCLUDED
read more*FIELD* TX

DESCRIPTION

The PML tumor suppressor protein is essential for the formation of a
dynamic macromolecular nuclear structure called the PML-nuclear body
(PML-NB). PML-NBs have also been referred to as nuclear domains-10,
Kremer bodies, and PML oncogenic domains. Unlike more specialized
subnuclear structures, PML-NBs are involved in diverse cellular
functions, including sequestration and release of proteins, mediation of
posttranslational modifications, and promotion of nuclear events in
response to various cellular stresses. The PML gene is involved in the
t(15;17) translocation of acute promyelocytic leukemia (APL; 612376),
which generates the oncogenic fusion protein PML-retinoic acid
receptor-alpha (RARA; 180240). PML-NBs are disrupted in APL and are thus
implicated in APL pathogenesis (Bernardi and Pandolfi, 2007; Salomoni et
al., 2008).

CLONING

In the process of analyzing the RARA gene in the t(15;17)(q22;q11.2-q12)
translocation specifically associated with APL, de The et al. (1990)
identified a novel gene on chromosome 15 involved with the RARA gene in
formation of a fusion product. This gene, which they called MYL for
'myelocytic leukemia,' was transcribed in the same direction as RARA on
the translocated chromosome. De The et al. (1990) identified a 144-bp
region, flanked by canonical splice acceptor and donor sequences, that
had a high probability of being an exon and showed no significant
similarity to any sequence in a protein data bank, thus suggesting that
MYL is a previously undescribed gene. In a later report, de The et al.
(1991) changed the name of the gene from MYL to PML. They reported,
furthermore, that the gene product contains a novel zinc finger motif
common to several DNA-binding proteins.

Goddard et al. (1991) demonstrated that PML is a putative zinc finger
protein and potential transcription factor that is commonly expressed,
with at least 3 major transcription products.

Goddard et al. (1995) cloned the murine Pml gene. The predicted amino
acid sequence of mouse Pml, a ring-finger protein, shows 80% similarity
to that of the human homolog, with greater than 90% similarity in the
proposed functional domains.

MAPPING

The PML gene maps to chromosome 15q22 (de The et al., 1990).

Goddard et al. (1995) mapped the mouse Pml gene to a region of
chromosome 9 with known homology of synteny to the region of 15q where
PML is located.

GENE FUNCTION

While PML does not colocalize with proliferating cell nuclear antigen
(PCNA; 176740) or spliceosomes, Dyck et al. (1994) showed that it is
part of a macromolecular structure, composed of at least 4 nuclear
proteins, that is adhered to the nuclear matrix. This structure shows a
labeling pattern resembling spheres that vary in both size and number
among individual cells of a given cell line. PML-RAR expression appears
to disrupt the integrity of these structures (referred to by Dyck et al.
(1994) as PML oncogenic domains, or PODs) and thus appears to be the
possible cause of their altered morphology. Retinoid treatment leads to
a striking reassembly of the POD, which in turn is linked to
differentiation of the leukemic cells. These results identified a novel
macromolecular nuclear structure and suggested that it may serve as a
target of cellular transformation.

From their analysis of the phosphoamino acids of the PML protein, Chang
et al. (1995) concluded that both tyrosine and serine residues are
phosphorylated. To investigate whether expression of the PML protein is
cell cycle related, HeLa cells synchronized at various phases of the
cell cycle were analyzed by immunofluorescence staining and confocal
microscopy. They found that PML was expressed at a lower level in S, G2,
and M phases and at a significantly higher level in G1 phase. Other
studies showed that PML is a phosphoprotein and is associated with the
nuclear matrix. Chang et al. (1995) noted that PML shares many
properties with tumor suppressors such as RB (614041).

Fusion of PML and TIF1A (603406) to RARA and BRAF (164757),
respectively, results in the production of PML-RAR-alpha and
TIF1-alpha-B-RAF (T18) oncoproteins. Zhong et al. (1999) showed that
PML, TIF1-alpha, and RXR-alpha (180245)/RAR-alpha function together in a
retinoic acid-dependent transcription complex. Zhong et al. (1999) found
that PML acts as a ligand-dependent coactivator of RXR-alpha/RARA-alpha.
PML interacts with TIF1-alpha and CREB-binding protein (CBP; 600140). In
PML -/- cells, the retinoic acid-dependent induction of genes such as
RARB2, and the ability of TIF1-alpha and CBP to act as transcriptional
coactivators on retinoic acid, are impaired. Zhong et al. (1999) showed
that both PML and TIF1-alpha are growth suppressors required for the
growth-inhibitory activity of retinoic acid. T18, similar to
PML-RAR-alpha, disrupts the retinoic acid-dependent activity of this
complex in a dominant-negative manner, resulting in a growth advantage.
PML-RAR-alpha was the first example of an oncoprotein generated by the
fusion of 2 molecules participating in the same pathway, specifically
the fusion of a transcription factor to one of its own cofactors. Since
the PML and RAR-alpha pathways converge at the transcriptional level,
there is no need for a double-dominant-negative product to explain the
pathogenesis of APL.

Pearson et al. (2000) reported that the tumor suppressor PML regulates
the p53 response to oncogenic signals. Pearson et al. (2000) found that
oncogenic RAS (190020) upregulates PML expression, and that
overexpression of PML induces senescence in a p53-dependent manner. p53
is acetylated at lysine-382 upon RAS expression, an event that is
essential for its biologic function. RAS induces relocalization of p53
and the CBP acetyltransferase within the PML nuclear bodies and induces
the formation of a trimeric p53-PML-CBP complex. Lastly, RAS-induced p53
acetylation, p53-CBP complex stabilization, and senescence are lost in
PML -/- fibroblasts. Pearson et al. (2000) concluded that their data
established a link between PML and p53 and indicated that integrity of
the PML bodies is required for p53 acetylation and senescence upon
oncogene expression.

Khan et al. (2001) showed that PML interacts with multiple corepressors
(SKI (164780), NCOR, and Sin3A (607776)) and histone deacetylase-1
(HDAC1; 601241), and that this interaction is required for
transcriptional repression mediated by the tumor suppressor MAD
(600021). PML-RARA has the 2 corepressor-interacting sites and inhibits
MAD-mediated repression, suggesting that aberrant binding of PML-RARA to
the corepressor complexes may lead to abrogation of the corepressor
function. The authors suggested that these mechanisms may contribute to
events leading to leukemogenesis.

Turelli et al. (2001) showed that incoming retroviral preintegration
complexes trigger the exportin (602559)-mediated cytoplasmic export of
the SWI/SNF component INI1 (601607) and of the nuclear body constituent
PML. They further showed that the human immunodeficiency virus (HIV)
genome associates with these proteins before nuclear migration. In the
presence of arsenic, PML was sequestered in the nucleus, and the
efficiency of HIV-mediated transduction was markedly increased. These
results unveiled an unsuspected cellular response that interferes with
the early steps of HIV replication.

Yang et al. (2002) determined that PML and checkpoint kinase-2 (CHEK2;
604373) mediated p53 (191170)-independent apoptosis following gamma
irradiation of several human cell lines. Endogenous CHEK2 bound PML
within PML nuclear bodies. Following gamma irradiation, CHEK2
phosphorylated PML on ser117, causing dissociation of the 2 proteins.
Apoptosis through this mechanism also required ATM (208900). Yang et al.
(2002) concluded that this pathway to gamma irradiation-induced
apoptosis utilizes ATM, CHEK2, and PML. Overexpression of PML alone
caused apoptosis in U937 myeloid cells.

Lin et al. (2004) demonstrated that cytoplasmic PML is an essential
modulator of TGF-beta signaling. Primary cells from Pml-null mice are
resistant to TGF-beta-dependent growth arrest, induction of cellular
senescence, and apoptosis. These cells also have impaired
phosphorylation and nuclear translocation of the TGF-beta signaling
proteins Smad2 (601366) and Smad3 (603109), as well as impaired
induction of TGF-beta target genes. Expression of cytoplasmic Pml is
induced by TGF-beta. Furthermore, cytoplasmic Pml physically interacts
with Smad2, Smad3, and SMAD anchor for receptor activation (SARA;
603755), and is required for association of Smad2 and Smad3 with Sara
and for the accumulation of Sara and TGF-beta receptor (see 190181) in
the early endosome. The PML-RAR-alpha oncoprotein of acute promyelocytic
leukemia can antagonize cytoplasmic PML function, and acute
promyelocytic leukemia cells have defects in TGF-beta signaling similar
to those observed in Pml-null cells. Lin et al. (2004) concluded that
their findings identified cytoplasmic PML as a critical TGF-beta
receptor and further implicated deregulated TGF-beta signaling in cancer
pathogenesis.

Trotman et al. (2006) demonstrated that the PML tumor suppressor
prevents cancer by inactivating phosphorylated AKT (164730) inside the
nucleus. They found in a mouse model that Pml loss markedly accelerated
tumor onset, incidence, and progression in Pten (601728) heterozygous
mutants, and led to female sterility with features that recapitulate the
phenotype of Foxo3a knockout mice. Trotman et al. (2006) showed that PML
deficiency on its own leads to tumorigenesis in the prostate, a tissue
that is exquisitely sensitive to phosphorylated AKT levels, and
demonstrated that PML specifically recruits the AKT phosphatase PP2a
(see 603113) as well phosphorylated AKT into PML nuclear bodies.
Notably, Trotman et al. (2006) found that PML-null cells are impaired in
PP2a phosphatase activity towards AKT, and thus accumulate nuclear
phosphorylated AKT. As a consequence, the progressive reduction in PML
dose leads to inactivation of FOXO3A-mediated transcription of
proapoptotic BIM (603827) and the cell cycle inhibitor p27(KIP1)
(600778). Trotman et al. (2006) concluded that their results demonstrate
that PML orchestrates a nuclear tumor suppressor network for
inactivation of nuclear phosphorylated AKT, and thus highlight the
importance of AKT compartmentalization in human cancer pathogenesis and
treatment.

Bernardi et al. (2006) identified PML as a critical inhibitor of
neoangiogenesis (the formation of new blood vessels) in vivo, in both
ischemic and neoplastic conditions, through the control of protein
translation. Bernardi et al. (2006) demonstrated that in hypoxic
conditions PML acts as a negative regulator of the synthesis rate of
hypoxia-inducible factor 1-alpha (HIF1A; 603348) by repressing MTOR
(601231). PML physically interacts with MTOR and negatively regulates
its association with the small GTPase RHEB (601293) by favoring MTOR
nuclear accumulation. Notably, PML-null cells and tumors display higher
sensitivity both in vitro and in vivo to growth inhibition by rapamycin,
and lack of PML inversely correlates with phosphorylation of ribosomal
protein S6 (180460) and tumor angiogenesis in mouse and human tumors.
Thus, Bernardi et al. (2006) concluded that their findings identified
PML as a novel suppressor of mTOR and neoangiogenesis.

By yeast 2-hybrid analysis of a human fetal brain cDNA library, followed
by coimmunoprecipitation analysis, Kunapuli et al. (2006) found that
ZNF198 (ZMYM2; 602221) was covalently modified by SUMO1 (601912).
Confocal microscopy showed that a proportion of ZNF198 colocalized with
SUMO1 and PML in PML nuclear bodies, and coimmunoprecipitation analysis
revealed that all 3 proteins resided in a protein complex. Mutation of
the SUMO1-binding site of ZNF198 resulted in degradation of ZNF198,
nuclear dispersal of PML, and loss of punctate PML nuclear bodies.
Kunapuli et al. (2006) found that the MDA-MB-157 breast cancer cell
line, which has a deletion in chromosome 13q11 encompassing the ZNF198
gene, lacked PML nuclear bodies, although PML protein levels appeared
normal. The fusion protein ZNF198/FGFR1 (136350), which occurs in
atypical myeloproliferative disease (613523) and lacks the SUMO1-binding
site of ZNF198, could dimerize with wildtype ZNF198 and disrupt its
function. Expression of ZNF198/FGFR1 disrupted PML sumoylation and
nuclear body formation and resulted in cytoplasmic localization of
SUMO1. Kunapuli et al. (2006) concluded that sumoylation of ZNF198 is
required for PML nuclear body formation.

Ito et al. (2008) showed that PML is critical in the maintenance of
quiescent leukemia-initiating cells and normal hematopoietic stem cells.
They suggested that targeting PML may be an effective treatment for
prevention of relapse in CML (608232).

Song et al. (2008) found that PTEN was aberrantly localized in APL in
which PML function was disrupted by the PML-RARA fusion oncoprotein.
Treatment with drugs that triggered PML-RARA degradation restored
nuclear PTEN. PML opposed the activity of HAUSP (USP7; 602519) towards
PTEN through a mechanism involving DAXX (603186). Confocal microscopy
and immunohistochemistry demonstrated that HAUSP was overexpressed in
prostate cancer and that levels of HAUSP directly correlated with tumor
aggressiveness and with PTEN nuclear exclusion. Song et al. (2008)
concluded that a PML-HAUSP network controls PTEN deubiquitinylation and
subcellular localization, which is perturbed in human cancers.

Arsenic, an ancient drug used in traditional Chinese medicine, has
attracted worldwide interest because it shows substantial anticancer
activity in patients with acute promyelocytic leukemia (APL). Arsenic
trioxide exerts its therapeutic effect by promoting degradation of
PML-RARA. PML and PML-RARA degradation is triggered by their
sumoylation, but the mechanism by which arsenic trioxide induces this
posttranslational modification was unclear. Zhang et al. (2010) showed
that arsenic binds directly to cysteine residues in zinc fingers located
within the RBCC domain of PML-RARA and PML. Arsenic binding induces PML
oligomerization, which increases its interaction with the small
ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9 (601661),
resulting in enhanced sumoylation and degradation. Zhang et al. (2010)
concluded that the identification of PML as a direct target of arsenic
trioxide provides insights into the drug's mechanism of action and its
specificity for APL.

In mouse embryonic fibroblasts, Giorgi et al. (2010) found that
extranuclear Pml was specifically enriched at the endoplasmic reticulum
(ER) and at the mitochondria-associated membranes, signaling domains
involved in ER-to-mitochondria calcium ion transport and in induction of
apoptosis. They found Pml in complexes of large molecular size with the
inositol 1,4,5-triphosphate receptor (IP3R; 147265), protein kinase Akt
(164730), and protein phosphatase 2a (176915). Pml was essential for
Akt- and PP2a-dependent modulation of Ip3r phosphorylation and in turn
for Ip3r-mediated calcium ion release from the endoplasmic reticulum.
Giorgi et al. (2010) concluded that their findings provided a
mechanistic explanation for the pleiotropic role of Pml in apoptosis.

- Reviews of PML Function

Bernardi and Pandolfi (2007) reviewed the structure, dynamics, and
functions of PML-NBs.

Salomoni et al. (2008) reviewed the role of PML in tumor suppression.

- PML/RARA Fusion Protein

For information on the generation of PML/RARA fusion genes through
translocations associated with APL, see CYTOGENETICS.

Grignani et al. (1993) expressed the PML-RARA protein in U937 myeloid
precursor cells and showed that they lost the capacity to differentiate
under the action of stimuli such as vitamin D3 and transforming growth
factor beta-1 (TGFB1; 190180), acquired enhanced sensitivity to retinoic
acid, and exhibited a higher growth rate consequent to diminished
apoptotic cell death. These results provided evidence of biologic
activity of the fusion protein and recapitulated critical features of
the promyelocytic leukemia phenotype.

Lin et al. (1998) reported that the association of PLZF-RAR-alpha (see
176797) and PML-RAR-alpha with the histone deacetylase complex (see
605164) helps to determine both the development of APL and the ability
of patients to respond to retinoids. Consistent with these observations,
inhibitors of histone deacetylase dramatically potentiate
retinoid-induced differentiation of retinoic acid-sensitive, and restore
retinoid responses of retinoic acid-resistant, APL cell lines. Lin et
al. (1998) concluded that oncogenic retinoic acid receptors mediate
leukemogenesis through aberrant chromatin acetylation, and that
pharmacologic manipulation of nuclear receptor cofactors may be a useful
approach in the treatment of human disease.

Grignani et al. (1998) demonstrated that both PML-RAR-alpha and
PLZF-RAR-alpha fusion proteins recruit the nuclear corepressor (NCOR;
see 600849)-histone deacetylase complex through the RAR-alpha CoR box.
PLZF-RAR-alpha contains a second, retinoic acid-resistant binding site
in the PLZF amino-terminal region. High doses of retinoic acid release
histone deacetylase activity from PML-RAR-alpha, but not from
PLZF-RAR-alpha. Mutation of the NCOR binding site abolishes the ability
of PML-RAR-alpha to block differentiation, whereas inhibition of histone
deacetylase activity switches the transcriptional and biologic effects
of PLZF-RAR-alpha from being an inhibitor to an activator of the
retinoic acid signaling pathway. Therefore, Grignani et al. (1998)
concluded that recruitment of histone deacetylase is crucial to the
transforming potential of APL fusion proteins, and the different effects
of retinoic acid on the stability of the PML-RAR-alpha and
PLZF-RAR-alpha corepressor complexes determines the differential
response of APLs to retinoic acid.

RAR and acute myeloid leukemia-1 (AML1; 151385) transcription factors
are found in leukemias as fusion proteins with PML and ETO (CBFA2T1;
133435), respectively. Association of PML-RAR and AML1-ETO with the
NCOR-histone deacetylase complex is required to block hematopoietic
differentiation. Minucci et al. (2000) showed that PML-RAR and AML1-ETO
exist in vivo within high molecular weight nuclear complexes, reflecting
their oligomeric state. Oligomerization requires PML or ETO coiled-coil
regions and is responsible for abnormal recruitment of NCOR,
transcriptional repression, and impaired differentiation of primary
hematopoietic precursors. Fusion of RAR to a heterologous
oligomerization domain recapitulated the properties of PML-RAR,
indicating that oligomerization per se is sufficient to achieve
transforming potential. These results showed that oligomerization of a
transcription factor, imposing an altered interaction with
transcriptional coregulators, represents a novel mechanism of oncogenic
activation.

The recruitment of the nuclear receptor corepressor SMRT (NCOR2; 600848)
and subsequent repression of retinoid target genes is critical for the
oncogenic function of PML-RARA. Lin and Evans (2000) showed that the
ability of PML-RARA to form homodimers is both necessary and sufficient
for its increased binding efficiency to corepressor and its inhibitory
effects on hormonal responses in myeloid differentiation. Furthermore,
the authors found that altered stoichiometric interaction of SMRT with
PML-RARA homodimers may underlie these processes. An RXR mutant lacking
transactivation function AF2 recapitulated many biochemical and
functional properties of PML-RARA. Taken together, these results
indicated that altered dimerization of a transcription factor can be
directly linked to cellular transformation, and they implicated
dimerization interfaces of oncogenes as potential drug targets.

Pandolfi (2001) reviewed the roles of the RARA and PML genes in the
pathogenesis of APL and discussed the multiple oncogenic activities of
PML-RARA.

Di Croce et al. (2002) demonstrated that PML-RARA fusion protein induces
gene hypermethylation and silencing by recruiting DNA methyltransferases
to target promoters and that hypermethylation contributes to its
leukemogenic potential. Retinoic acid treatment induces promoter
demethylation, gene reexpression, and reversion of the transformed
phenotype. Di Croce et al. (2002) concluded that their results establish
a mechanistic link between genetic and epigenetic changes during
transformation and suggest that hypermethylation contributes to the
early steps of carcinogenesis.

The fusion protein PML-RARA initiates APL when expressed in the early
myeloid compartment of transgenic mice. Lane and Ley (2003) found that
PML-RARA was cleaved in several positions by a neutral serine protease
in a human myeloid cell line; purification revealed that the protease
was neutrophil elastase (ELA2; 130130). Immunofluorescence localization
studies suggested that cleavage of PML-RARA must have occurred within
the cell, perhaps within the nucleus. The functional importance of ELA2
for APL development was assessed in Ela2-deficient mice. More than 90%
of bone marrow PML-RARA-cleaving activity was lost in the absence of
Ela2, and Ela2-deficient animals, but not cathepsin G (116830)-deficient
animals, were protected from APL development. The authors determined
that primary mouse and human APL cells also contained ELA2-dependent
PML-RARA-cleaving activity. Lane and Ley (2003) concluded that, since
ELA2 is maximally produced in promyelocytes, it may play a role in APL
pathogenesis by facilitating the leukemogenic potential of PML-RARA.

Villa et al. (2006) found that MBD1 (156535) cooperated with PML-RARA in
transcriptional repression and cellular transformation in human cell
lines. PML-RARA recruited MBD1 to its target promoter through an HDAC3
(605166)-mediated mechanism. Binding of HDAC3 and MBD1 was not confined
to the target promoter, but was instead spread over the locus. Knockdown
of HDAC3 expression by RNA interference in acute promyelocytic leukemia
cells alleviated PML-RARA-induced promoter silencing. Furthermore,
retroviral expression of dominant-negative mutants of MBD1 in human
hematopoietic precursors interfered with PML-RARA-induced repression and
restored cell differentiation. Villa et al. (2006) concluded that
PML-RARA recruits an HDAC3-MBD1 complex to target promoters to establish
and maintain chromatin silencing.

CYTOGENETICS

- PML/RARA Fusion Gene

In the process of analyzing the RARA gene in the t(15;17)(q22;q11.2-q12)
translocation specifically associated with acute promyelocytic leukemia
(APL), de The et al. (1990) identified a novel gene on chromosome 15
involved with the RARA gene in formation of a fusion product. This gene,
which they called MYL, was transcribed in the same direction as RARA on
the translocated chromosome. In the chimeric gene, the promoter and
first exon of the RARA gene were replaced by part of the MYL gene. De
The et al. (1990) established that the translocation chromosome
generates an MYL-RARA chimeric transcript. The findings strongly
implicated RARA in leukemogenesis. The possibility was raised that the
altered retinoic acid receptor behaves as a dominant-negative mutant
that blocks the expression of retinoic acid target genes involved in
granulocytic differentiation. In a later report, de The et al. (1991)
changed the name of the gene from MYL to PML. The PML-RARA mRNA encoded
a predicted 106-kD chimeric protein containing most of the PML sequences
fused to a large part of the RARA gene, including its DNA- and
hormone-binding domains.

Goddard et al. (1991) determined that the PML breakpoints were clustered
in 2 regions on either side of an alternatively spliced exon. Although
leukemic cells with translocations characteristically expressed only 1
fusion product, both PML-RARA (on the 15q+ derivative chromosome) and
RARA-PML (on the 17q- derivative) were transcribed. The contribution of
PML to the oncogenicity of the fusion products was demonstrated by the
following: no mutations affecting RARA alone were observed in 20 APLs
analyzed; 2 APLs cytogenetically lacking t(15;17) chromosomes were found
to have rearrangements of both PML and RARA; and PML but not RARA was
molecularly rearranged in a variant APL translocation in which
chromosome 15 had been translocated to another chromosome with no
visible involvement of chromosome 17.

Tong et al. (1992) found that in 20 of 22 patients with a detectable MYL
rearrangement the breakpoints were clustered within a 4.4-kb segment,
which they designated MYL(bcr). The 2 remaining patients exhibited a
more 5-prime rearrangement at about 10-kb upstream of the MYL(bcr)
region, indicating the lack of at least one MYL gene exon in the
resulting MYL-RARA fusion gene.

Cleary (1991) pointed out that detection of the PML-RARA fusion links a
specific molecular defect in neoplasia with a characteristic biologic
and clinical response to pharmacologic therapy. It is a useful marker
for the diagnosis of APL and for the identification of patients who may
benefit from retinoid treatment.

PML, the gene involved in the breakpoint on chromosome 15, is a putative
transcription factor: it contains a cysteine-rich motif that resembles a
zinc finger DNA-binding domain common to several classes of
transcriptional factors. Two fusion genes, PML-RARA and RARA-PML, are
formed as a result of the characteristic translocation in APL.
Heterogeneity of the chromosome 15 breakpoints accounts for the diverse
architecture of the PML-RARA mRNAs isolated from different APL patients,
and alternative splicing of PML exons gives rise to multiple isoforms of
the PML-RARA mRNAs even within a single patient. Alcalay et al. (1992)
investigated the organization and expression pattern of the RARA/PML
gene in a series of APL patients. A RARA-PML transcript was present in
most but not all APL patients. Among 70 patients with APL, Diverio et
al. (1992) found an abnormality in intron 2 of the RARA gene in all
cases, with clustering of rearrangements within the 20-kb intronic
region separating exons 2 and 3. A curious difference was found in the
location of breakpoints in males and females: breakpoints at the 5-prime
end of intron 2 of the RARA gene occurred in females and 3-prime
breakpoints predominated in males.

Stock et al. (2000) pointed out that breakpoints in chromosomes 15 and
17 leading to the translocation associated with APL had been described
as located between 15q22 and 15q26, and between 17q11 and 17q25. Most
studies using FISH had indicated the chromosome 15 breakpoint to be in
15q22. Stock et al. (2000) used a combination of G-banding, FISH, and
chromosome microdissection/reverse in situ hybridization to map the
breakpoints precisely to 15q24 and 17q21.1.

Zaccaria et al. (2002) studied a rare example of cryptic translocation
causing APL. Conventional cytogenetics showed a normal karyotype; PCR
showed a typical PML-RARA rearrangement in exon 1. FISH analysis
revealed that a submicroscopic part of chromosome 15 had been inserted
into 17q. Zaccaria et al. (2002) reviewed other cases of cryptic
translocation; their report appeared to be the first in which both pairs
of chromosomes 15 and 17 were cytogenetically normal and a PML-RARA
fusion gene, discovered after FISH analysis, was located on chromosome
17. A poor response to ATRA therapy was postulated to have a
relationship to the atypical translocation.

Abreu e Lima et al. (2005) described a 47-year-old woman with acute
myeloid leukemia who had simultaneous expression of the PML/RARA and the
AML1/ETO (133435) fusion genes. Despite prolonged use of therapeutic
doses of ATRA plus chemotherapy, the patient did not achieve remission,
in contrast to the experience of most patients with such fusion genes.
Conventional cytogenetics in this case showed the presence of only the
t(8;21) translocation. In previous reports of coexpression of these 2
fusion genes there was evidence of the presence of 2 or 3 distinct
leukemic clones harboring either or both chromosomal translocations.

ANIMAL MODEL

Brown et al. (1997) established a transgenic mouse model that documented
the ability of the chimeric PML-RARA gene to initiate leukemogenesis.
The mice developed 2 currently unrelated abnormalities. The first was a
severe papillomatosis of the skin; the second was a disturbance of
hematopoiesis that presented as a partial block of differentiation in
the neutrophil lineage of the transgenic mice and then progressed at low
frequency to overt APL. The leukemia appeared to be a faithful
reproduction of the human disease, including a therapeutic response to
retinoic acid that reflected differentiation of the leukemic cells. Both
the preleukemic state and the overt leukemia could be transplanted into
nontransgenic hosts. Brown et al. (1997) commented that the model should
be useful for exploring the pathogenesis and treatment of APL.

From studies in mice with disruption of the Pml gene, Wang et al. (1998)
demonstrated that normally, PML regulates hemopoietic differentiation
and controls cell growth and tumorigenesis. PML function is essential
for the tumor-growth-suppressive activity of retinoic acid (RA) and for
its ability to induce terminal myeloid differentiation of precursor
cells. PML was needed for the RA-dependent transactivation of the
p21(Waf1/Cip1) gene (116899), which regulates cell cycle progression and
cellular differentiation. These results provided a framework for
understanding the molecular pathogenesis of APL. Whereas APL might
result from the functional interference of PML/RARA with 2 independent
pathways, PML and RXR/RAR, Wang et al. (1998) showed that these proteins
act, at least in part, in the same pathway. Thus, by simultaneously
interacting with RXR and PML, the fusion gene product may inactivate
this pathway at multiple levels, leading to the proliferative advantage
and the block of hemopoietic differentiation that characterize APL.

David et al. (1997) generated an inducible line of transgenic mice in
which the expression of PML-RARA is driven by the metallothionein
promoter. After 5 days zinc stimulation, 27 of 54 mice developed hepatic
preneoplasia and neoplasia including foci of basophilic hepatocytes,
dysplasia, and carcinoma, with a significantly higher incidence of
lesions in females than in males. The rapid onset of liver pathologies
was dependent on overexpression of the transgene, since it was not
detected in noninduced transgenic animals of the same age. The PML-RARA
protein was always present in altered tissues at much higher levels than
in the surrounding normal liver tissues. In addition, overexpression of
PML-RARA resulted in a strong proliferative response in the hepatocytes.
David et al. (1997) concluded that overexpression of PML-RARA
deregulates subproliferation and can induce tumorigenic changes in vivo.

In an animal model of acute promyelocytic leukemia, Padua et al. (2003)
developed a DNA-based vaccine by fusing the human PML-RARA oncogene to
tetanus fragment C (FrC) sequences. Padua et al. (2003) showed for the
first time that a DNA vaccine specifically targeted to an oncoprotein
can have a pronounced effect on survival, both alone and in combination
with all-trans retinoic acid (ATRA). The survival advantage was
concomitant with time-dependent antibody production and an increase in
interferon-gamma (IFNG; 147570). Padua et al. (2003) also showed that
ATRA therapy on its own triggered an immune response in this model. When
DNA vaccination and conventional ATRA therapy were combined, they
induced protective immune responses against leukemia progression in
mice. Padua et al. (2003) concluded that this may provide a new approach
to improve clinical outcome in human leukemia.

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*FIELD* CN
Ada Hamosh - updated: 1/31/2011
Patricia A. Hartz - updated: 10/19/2010
Ada Hamosh - updated: 5/25/2010
Paul J. Converse - updated: 11/19/2008
Matthew B. Gross - updated: 10/14/2008
Matthew B. Gross - reorganized: 10/13/2008
Ada Hamosh - updated: 7/9/2008
Ada Hamosh - updated: 9/8/2006
Ada Hamosh - updated: 7/24/2006
Patricia A. Hartz - updated: 3/29/2006
Victor A. McKusick - updated: 3/21/2005
Victor A. McKusick - updated: 1/25/2005
Ada Hamosh - updated: 9/29/2004
Ada Hamosh - updated: 1/8/2004
Stylianos E. Antonarakis - updated: 11/19/2003
Patricia A. Hartz - updated: 3/14/2003
Victor A. McKusick - updated: 3/3/2003
Ada Hamosh - updated: 2/12/2002
Stylianos E. Antonarakis - updated: 7/3/2001
George E. Tiller - updated: 6/19/2001
Ada Hamosh - updated: 5/1/2001
Ada Hamosh - updated: 4/30/2001
Ada Hamosh - updated: 7/12/2000
Stylianos E. Antonarakis - updated: 6/21/2000
Ada Hamosh - updated: 5/29/2000
Ada Hamosh - updated: 11/2/1999
Victor A. McKusick - updated: 9/15/1999
Victor A. McKusick - updated: 10/1/1998
Victor A. McKusick - updated: 3/2/1998
Victor A. McKusick - updated: 4/21/1997

*FIELD* CD
Victor A. McKusick: 11/30/1990

*FIELD* ED
terry: 03/14/2013
carol: 6/17/2011
alopez: 2/4/2011
terry: 1/31/2011
wwang: 11/22/2010
mgross: 10/19/2010
alopez: 5/26/2010
terry: 5/25/2010
mgross: 11/19/2008
mgross: 10/28/2008
mgross: 10/14/2008
mgross: 10/13/2008
wwang: 7/17/2008
terry: 7/9/2008
alopez: 9/19/2006
terry: 9/8/2006
alopez: 7/27/2006
terry: 7/24/2006
mgross: 3/29/2006
carol: 4/4/2005
wwang: 3/30/2005
wwang: 3/23/2005
terry: 3/21/2005
tkritzer: 3/17/2005
terry: 1/25/2005
tkritzer: 10/1/2004
terry: 9/29/2004
tkritzer: 1/12/2004
terry: 1/8/2004
mgross: 11/19/2003
mgross: 5/12/2003
mgross: 3/18/2003
terry: 3/14/2003
tkritzer: 3/10/2003
terry: 3/3/2003
alopez: 2/12/2002
terry: 2/12/2002
terry: 11/15/2001
mgross: 7/3/2001
cwells: 6/20/2001
cwells: 6/19/2001
alopez: 5/1/2001
alopez: 4/30/2001
alopez: 7/12/2000
mgross: 6/21/2000
alopez: 6/2/2000
terry: 5/29/2000
alopez: 11/3/1999
alopez: 11/2/1999
mgross: 9/23/1999
terry: 9/15/1999
carol: 10/6/1998
terry: 10/1/1998
dkim: 9/11/1998
alopez: 3/6/1998
terry: 3/2/1998
alopez: 7/9/1997
carol: 6/20/1997
jenny: 4/21/1997
terry: 4/12/1997
mark: 11/30/1995
mark: 10/5/1995
carol: 8/13/1992
carol: 6/16/1992
carol: 5/28/1992
supermim: 3/16/1992

RBCC Red Blood Cell Collection

Full text data of PML