RBCC Red Blood Cell Collection

NPM1 (NPM) [Confidence: low (only semi-automatic identification from reviews)]
Nucleophosmin; NPM (Nucleolar phosphoprotein B23; Nucleolar protein NO38; Numatrin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P06748
ID NPM_HUMAN Reviewed; 294 AA.
AC P06748; A8K3N7; B5BU00; D3DQL6; P08693; Q12826; Q13440; Q13441;
read moreAC Q14115; Q5EU94; Q5EU95; Q5EU96; Q5EU97; Q5EU98; Q5EU99; Q6V962;
AC Q8WTW5; Q96AT6; Q96DC4; Q96EA5; Q9BYG9; Q9UDJ7;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1990, sequence version 2.
DT 22-JAN-2014, entry version 176.
DE RecName: Full=Nucleophosmin;
DE Short=NPM;
DE AltName: Full=Nucleolar phosphoprotein B23;
DE AltName: Full=Nucleolar protein NO38;
DE AltName: Full=Numatrin;
GN Name=NPM1; Synonyms=NPM;
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 1).
RC TISSUE=Placenta;
RX PubMed=2713355; DOI=10.1021/bi00429a017;
RA Chan W.-Y., Liu Q.R., Borjigin J., Busch H., Rennert O.M., Tease L.A.,
RA Chan P.-K.;
RT "Characterization of the cDNA encoding human nucleophosmin and studies
RT of its role in normal and abnormal growth.";
RL Biochemistry 28:1033-1039(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=B-cell lymphoma;
RX PubMed=2775293; DOI=10.1016/0006-291X(89)92100-1;
RA Li X., McNeilage L.J., Whittingham S.;
RT "The nucleotide sequence of a human cDNA encoding the highly conserved
RT nucleolar phosphoprotein B23.";
RL Biochem. Biophys. Res. Commun. 163:72-78(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Amnion;
RX PubMed=2478125; DOI=10.1016/0006-291X(89)91699-9;
RA Zhang X.T., Thomis D.C., Samuel C.E.;
RT "Isolation and characterization of a molecular cDNA clone of a human
RT mRNA from interferon-treated cells encoding nucleolar protein B23,
RT numatrin.";
RL Biochem. Biophys. Res. Commun. 164:176-184(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=9092633; DOI=10.1093/nar/25.6.1225;
RA Chan P.-K., Chan F.Y., Morris S.W., Xie Z.;
RT "Isolation and characterization of the human nucleophosmin/B23 (NPM)
RT gene: identification of the YY1 binding site at the 5' enhancer
RT region.";
RL Nucleic Acids Res. 25:1225-1232(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Okuwaki M., Nagata K.;
RT "Human homologue of Rat B23.2.";
RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, AND
RP INVOLVEMENT IN ACUTE MYELOGENOUS LEUKEMIA.
RC TISSUE=Bone marrow;
RX PubMed=15659725; DOI=10.1056/NEJMoa041974;
RA Falini B., Mecucci C., Tiacci E., Alcalay M., Rosati R.,
RA Pasqualucci L., La Starza R., Diverio D., Colombo E., Santucci A.,
RA Bigerna B., Pacini R., Pucciarini A., Liso A., Vignetti M., Fazi P.,
RA Meani N., Pettirossi V., Saglio G., Mandelli F., Lo-Coco F.,
RA Pelicci P.-G., Martelli M.F.;
RT "Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal
RT karyotype.";
RL N. Engl. J. Med. 352:254-266(2005).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=16574551; DOI=10.1016/S1470-2045(06)70661-1;
RA Bolli N., Galimberti S., Martelli M.P., Tabarrini A., Roti G.,
RA Mecucci C., Martelli M.F., Petrini M., Falini B.;
RT "Cytoplasmic nucleophosmin in myeloid sarcoma occurring 20 years after
RT diagnosis of acute myeloid leukaemia.";
RL Lancet Oncol. 7:350-352(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RA Lu L., Huang X.Y., Yin L.L., Xu M., Li J.M., Zhou Z.M., Sha J.H.;
RT "Cloning of a new transcript of nucleophosmin in testis.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Embryo;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=19054851; DOI=10.1038/nmeth.1273;
RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H.,
RA Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M.,
RA Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T.,
RA Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A.,
RA Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K.,
RA Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S.,
RA Isogai T., Imai J., Watanabe S., Nomura N.;
RT "Human protein factory for converting the transcriptome into an in
RT vitro-expressed proteome.";
RL Nat. Methods 5:1011-1017(2008).
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Bone marrow, Brain, Kidney, Lung, Prostate, Testis, and
RC Urinary bladder;
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 [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-133, AND CHROMOSOMAL TRANSLOCATION
RP WITH RARA.
RC TISSUE=Bone marrow;
RX PubMed=8562957;
RA Redner R.L., Rush E.A., Faas S., Rudert W.A., Corey S.J.;
RT "The t(5;17) variant of acute promyelocytic leukemia expresses a
RT nucleophosmin-retinoic acid receptor fusion.";
RL Blood 87:882-886(1996).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-117, AND CHROMOSOMAL TRANSLOCATION
RP WITH ALK.
RC TISSUE=T-cell lymphoma;
RX PubMed=8122112; DOI=10.1126/science.8122112;
RA Morris S.W., Kirstein M.N., Valentine M.B., Dittmer K.G.,
RA Shapiro D.N., Saltman D.L., Look A.T.;
RT "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in
RT non-Hodgkin's lymphoma.";
RL Science 263:1281-1284(1994).
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-117, AND CHROMOSOMAL TRANSLOCATION
RP WITH ALK.
RC TISSUE=Lymphoma;
RX PubMed=8633037; DOI=10.1073/pnas.93.9.4181;
RA Fujimoto J., Shiota M., Iwahara T., Seki N., Satoh H., Mori S.,
RA Yamamoto T.;
RT "Characterization of the transforming activity of p80, a
RT hyperphosphorylated protein in a Ki-1 lymphoma cell line with
RT chromosomal translocation t(2;5).";
RL Proc. Natl. Acad. Sci. U.S.A. 93:4181-4186(1996).
RN [17]
RP PROTEIN SEQUENCE OF 1-24; 33-101; 104-141; 240-248 AND 278-291,
RP ACETYLATION AT MET-1, PHOSPHORYLATION AT SER-125, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [18]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 15-294 (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=2602120;
RA Hale T.K., Mansfield B.C.;
RT "Nucleotide sequence of a cDNA clone representing a third allele of
RT human protein B23.";
RL Nucleic Acids Res. 17:10112-10112(1989).
RN [19]
RP PROTEIN SEQUENCE OF 33-54.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [20]
RP PROTEIN SEQUENCE OF 34-42; 50-67; 137-151; 218-227; 252-266 AND
RP 277-286 (ISOFORM 1), AND INTERACTION WITH HTLV1 REX PROTEIN.
RX PubMed=8314759;
RA Adachi Y., Copeland T.D., Hatanaka M., Oroszlan S.;
RT "Nucleolar targeting signal of Rex protein of human T-cell leukemia
RT virus type I specifically binds to nucleolar shuttle protein B-23.";
RL J. Biol. Chem. 268:13930-13934(1993).
RN [21]
RP PROTEIN SEQUENCE OF 33-42; 213-221; 251-257 AND 268-274, FUNCTION,
RP INTERACTION WITH EIF2AK2, AND PHOSPHORYLATION.
RX PubMed=12882984; DOI=10.1074/jbc.M301392200;
RA Pang Q., Christianson T.A., Koretsky T., Carlson H., David L.,
RA Keeble W., Faulkner G.R., Speckhart A., Bagby G.C.;
RT "Nucleophosmin interacts with and inhibits the catalytic function of
RT eukaryotic initiation factor 2 kinase PKR.";
RL J. Biol. Chem. 278:41709-41717(2003).
RN [22]
RP PROTEIN SEQUENCE OF 115-134.
RX PubMed=3944116;
RA Chan P.-K., Aldrich M.B., Cook R.G., Busch H.;
RT "Amino acid sequence of protein B23 phosphorylation site.";
RL J. Biol. Chem. 261:1868-1872(1986).
RN [23]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 213-294 (ISOFORM 1), AND PROTEIN
RP SEQUENCE OF 227-294.
RX PubMed=2429957;
RA Chan P.-K., Chan W.-Y., Yung B.Y.M., Cook R.G., Aldrich M.B., Ku D.,
RA Goldknopf I.L., Busch H.;
RT "Amino acid sequence of a specific antigenic peptide of protein B23.";
RL J. Biol. Chem. 261:14335-14341(1986).
RN [24]
RP ADP-RIBOSYLATION.
RX PubMed=7631008;
RA Ramsamooj P., Notario V., Dritschilo A.;
RT "Modification of nucleolar protein B23 after exposure to ionizing
RT radiation.";
RL Radiat. Res. 143:158-164(1995).
RN [25]
RP CHROMOSOMAL TRANSLOCATION WITH MLF1.
RX PubMed=8570204;
RA Yoneda-Kato N., Look A.T., Kirstein M.N., Valentine M.B.,
RA Raimondi S.C., Cohen K.J., Carroll A.J., Morris S.W.;
RT "The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid
RT leukemia produces a novel fusion gene, NPM-MLF1.";
RL Oncogene 12:265-275(1996).
RN [26]
RP PHOSPHORYLATION BY CDK2.
RX PubMed=11051553; DOI=10.1016/S0092-8674(00)00093-3;
RA Okuda M., Horn H.F., Tarapore P., Tokuyama Y., Smulian A.G.,
RA Chan P.K., Knudsen E.S., Hofmann I.A., Snyder J.D., Bove K.E.,
RA Fukasawa K.;
RT "Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome
RT duplication.";
RL Cell 103:127-140(2000).
RN [27]
RP INTERACTION WITH HEPATITIS DELTA VIRUS S-HDAG.
RX PubMed=11309377; DOI=10.1074/jbc.M010087200;
RA Huang W.H., Yung B.Y., Syu W.J., Lee Y.H.;
RT "The nucleolar phosphoprotein B23 interacts with hepatitis delta
RT antigens and modulates the hepatitis delta virus RNA replication.";
RL J. Biol. Chem. 276:25166-25175(2001).
RN [28]
RP MUTAGENESIS OF THR-199; THR-219; THR-234 AND THR-237.
RX PubMed=12058066; DOI=10.1091/mbc.02-03-0036;
RA Okuwaki M., Tsujimoto M., Nagata K.;
RT "The RNA binding activity of a ribosome biogenesis factor,
RT nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-
RT dependent kinase and by association with its subtype.";
RL Mol. Biol. Cell 13:2016-2030(2002).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION [LARGE
RP SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=12429849; DOI=10.1091/mbc.E02-05-0271;
RA Scherl A., Coute Y., Deon C., Calle A., Kindbeiter K., Sanchez J.-C.,
RA Greco A., Hochstrasser D.F., Diaz J.-J.;
RT "Functional proteomic analysis of human nucleolus.";
RL Mol. Biol. Cell 13:4100-4109(2002).
RN [30]
RP REVIEW.
RX PubMed=12214246; DOI=10.1038/sj.onc.1205708;
RA Okuda M.;
RT "The role of nucleophosmin in centrosome duplication.";
RL Oncogene 21:6170-6174(2002).
RN [31]
RP SUBCELLULAR LOCATION, PHOSPHORYLATION, AND INTERACTION WITH NEK2.
RX PubMed=15388344; DOI=10.1016/j.febslet.2004.08.047;
RA Yao J., Fu C., Ding X., Guo Z., Zenreski A., Chen Y., Ahmed K.,
RA Liao J., Dou Z., Yao X.;
RT "Nek2A kinase regulates the localization of numatrin to centrosome in
RT mitosis.";
RL FEBS Lett. 575:112-118(2004).
RN [32]
RP PHOSPHORYLATION AT SER-4 BY PLK1.
RX PubMed=15190079; DOI=10.1074/jbc.M403264200;
RA Zhang H., Shi X., Paddon H., Hampong M., Dai W., Pelech S.;
RT "B23/nucleophosmin serine 4 phosphorylation mediates mitotic functions
RT of polo-like kinase 1.";
RL J. Biol. Chem. 279:35726-35734(2004).
RN [33]
RP INTERACTION WITH RPGR.
RX PubMed=15772089; DOI=10.1093/hmg/ddi129;
RA Shu X., Fry A.M., Tulloch B., Manson F.D., Crabb J.W., Khanna H.,
RA Faragher A.J., Lennon A., He S., Trojan P., Giessl A., Wolfrum U.,
RA Vervoort R., Swaroop A., Wright A.F.;
RT "RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal
RT bodies and interacts with nucleophosmin.";
RL Hum. Mol. Genet. 14:1183-1197(2005).
RN [34]
RP ACETYLATION AT LYS-212; LYS-229; LYS-230; LYS-250; LYS-257 AND
RP LYS-292, AND FUNCTION AS A CHAPERONE.
RX PubMed=16107701; DOI=10.1128/MCB.25.17.7534-7545.2005;
RA Swaminathan V., Kishore A.H., Febitha K.K., Kundu T.K.;
RT "Human histone chaperone nucleophosmin enhances acetylation-dependent
RT chromatin transcription.";
RL Mol. Cell. Biol. 25:7534-7545(2005).
RN [35]
RP SUMOYLATION AT LYS-230 AND LYS-263.
RX PubMed=15897463; DOI=10.1073/pnas.0502978102;
RA Tago K., Chiocca S., Sherr C.J.;
RT "Sumoylation induced by the Arf tumor suppressor: a p53-independent
RT function.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:7689-7694(2005).
RN [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70 AND THR-95, AND MASS
RP 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 ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-150; LYS-154 AND LYS-212,
RP AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16916647; DOI=10.1016/j.molcel.2006.06.026;
RA Kim S.C., Sprung R., Chen Y., Xu Y., Ball H., Pei J., Cheng T.,
RA Kho Y., Xiao H., Xiao L., Grishin N.V., White M., Yang X.-J., Zhao Y.;
RT "Substrate and functional diversity of lysine acetylation revealed by
RT a proteomics survey.";
RL Mol. Cell 23:607-618(2006).
RN [38]
RP FUNCTION, AND INTERACTION WITH ROCK2.
RX PubMed=17015463; DOI=10.1128/MCB.01383-06;
RA Ma Z., Kanai M., Kawamura K., Kaibuchi K., Ye K., Fukasawa K.;
RT "Interaction between ROCK II and nucleophosmin/B23 in the regulation
RT of centrosome duplication.";
RL Mol. Cell. Biol. 26:9016-9034(2006).
RN [39]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70; THR-199 AND SER-254,
RP AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [40]
RP INTERACTION WITH NSUN2.
RX PubMed=17215513; DOI=10.1091/mbc.E06-11-1021;
RA Sakita-Suto S., Kanda A., Suzuki F., Sato S., Takata T., Tatsuka M.;
RT "Aurora-B regulates RNA methyltransferase NSUN2.";
RL Mol. Biol. Cell 18:1107-1117(2007).
RN [41]
RP INTERACTION WITH SENP3, AND MUTAGENESIS OF LYS-263.
RX PubMed=18259216; DOI=10.1038/embor.2008.3;
RA Haindl M., Harasim T., Eick D., Muller S.;
RT "The nucleolar SUMO-specific protease SENP3 reverses SUMO modification
RT of nucleophosmin and is required for rRNA processing.";
RL EMBO Rep. 9:273-279(2008).
RN [42]
RP INTERACTION WITH SENP3, AND SUBCELLULAR LOCATION.
RX PubMed=19015314; DOI=10.1083/jcb.200807185;
RA Yun C., Wang Y., Mukhopadhyay D., Backlund P., Kolli N., Yergey A.,
RA Wilkinson K.D., Dasso M.;
RT "Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO
RT pathway through SENP3 and SENP5 proteases.";
RL J. Cell Biol. 183:589-595(2008).
RN [43]
RP REVIEW.
RX PubMed=18024471; DOI=10.1093/jb/mvm222;
RA Okuwaki M.;
RT "The structure and functions of NPM1/Nucleophosmin/B23, a
RT multifunctional nucleolar acidic protein.";
RL J. Biochem. 143:441-448(2008).
RN [44]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70; SER-125 AND THR-279,
RP AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [45]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70 AND SER-125, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [46]
RP FUNCTION.
RX PubMed=18809582; DOI=10.1128/MCB.01548-07;
RA Maggi L.B. Jr., Kuchenruether M., Dadey D.Y., Schwope R.M.,
RA Grisendi S., Townsend R.R., Pandolfi P.P., Weber J.D.;
RT "Nucleophosmin serves as a rate-limiting nuclear export chaperone for
RT the Mammalian ribosome.";
RL Mol. Cell. Biol. 28:7050-7065(2008).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70; THR-75; THR-95;
RP SER-125; SER-139; THR-234; THR-237 AND SER-243, 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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [49]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [50]
RP FUNCTION, INTERACTION WITH APEX1, MASS SPECTROMETRY, AND SUBCELLULAR
RP LOCATION.
RX PubMed=19188445; DOI=10.1128/MCB.01337-08;
RA Vascotto C., Fantini D., Romanello M., Cesaratto L., Deganuto M.,
RA Leonardi A., Radicella J.P., Kelley M.R., D'Ambrosio C., Scaloni A.,
RA Quadrifoglio F., Tell G.;
RT "APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in
RT the rRNA quality control process.";
RL Mol. Cell. Biol. 29:1834-1854(2009).
RN [51]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [52]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70 AND SER-125, 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 [53]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-32; LYS-150; LYS-257;
RP LYS-267 AND LYS-273, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [54]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH RPS10.
RX PubMed=20159986; DOI=10.1074/jbc.M110.103911;
RA Ren J., Wang Y., Liang Y., Zhang Y., Bao S., Xu Z.;
RT "Methylation of ribosomal protein S10 by protein-arginine
RT methyltransferase 5 regulates ribosome biogenesis.";
RL J. Biol. Chem. 285:12695-12705(2010).
RN [55]
RP FUNCTION, PHOSPHORYLATION AT SER-4 BY PLK2, AND MUTAGENESIS OF SER-4;
RP THR-95; SER-125 AND THR-199.
RX PubMed=20352051; DOI=10.1371/journal.pone.0009849;
RA Krause A., Hoffmann I.;
RT "Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4
RT triggers centriole duplication.";
RL PLoS ONE 5:E9849-E9849(2010).
RN [56]
RP PHOSPHORYLATION AT THR-199 BY CDK6.
RX PubMed=20333249; DOI=10.1371/journal.ppat.1000818;
RA Sarek G., Jaerviluoma A., Moore H.M., Tojkander S., Vartia S.,
RA Biberfeld P., Laiho M., Ojala P.M.;
RT "Nucleophosmin phosphorylation by v-cyclin-CDK6 controls KSHV
RT latency.";
RL PLoS Pathog. 6:E1000818-E1000818(2010).
RN [57]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-4; SER-10; SER-70; THR-95; SER-125; SER-137;
RP SER-139; THR-199; SER-242; SER-243; SER-254; SER-260 AND THR-279, 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 [58]
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 [59]
RP FUNCTION, AND INTERACTION WITH BRCA2.
RX PubMed=21084279; DOI=10.1158/0008-5472.CAN-10-0030;
RA Wang H.F., Takenaka K., Nakanishi A., Miki Y.;
RT "BRCA2 and nucleophosmin coregulate centrosome amplification and form
RT a complex with the Rho effector kinase ROCK2.";
RL Cancer Res. 71:68-77(2011).
RN [60]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CENPW.
RX PubMed=22002061; DOI=10.1074/jbc.M111.228411;
RA Chun Y., Park B., Koh W., Lee S., Cheon Y., Kim R., Che L., Lee S.;
RT "New centromeric component CENP-W is an RNA-associated nuclear matrix
RT protein that interacts with nucleophosmin/B23 protein.";
RL J. Biol. Chem. 286:42758-42769(2011).
RN [61]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-4; SER-70; SER-125; SER-227; SER-243 AND
RP SER-254, 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 [62]
RP X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 9-124.
RX PubMed=17879352; DOI=10.1002/prot.21504;
RA Lee H.H., Kim H.S., Kang J.Y., Lee B.I., Ha J.Y., Yoon H.J., Lim S.O.,
RA Jung G., Suh S.W.;
RT "Crystal structure of human nucleophosmin-core reveals plasticity of
RT the pentamer-pentamer interface.";
RL Proteins 69:672-678(2007).
RN [63]
RP STRUCTURE BY NMR OF 243-294, AND MUTAGENESIS OF LYS-248; LYS-250;
RP PHE-268; PHE-276; TRP-288 AND TRP-290.
RX PubMed=18511415; DOI=10.1074/jbc.M801706200;
RA Grummitt C.G., Townsley F.M., Johnson C.M., Warren A.J., Bycroft M.;
RT "Structural consequences of nucleophosmin mutations in acute myeloid
RT leukemia.";
RL J. Biol. Chem. 283:23326-23332(2008).
CC -!- FUNCTION: Involved in diverse cellular processes such as ribosome
CC biogenesis, centrosome duplication, protein chaperoning, histone
CC assembly, cell proliferation, and regulation of tumor suppressors
CC p53/TP53 and ARF. Binds ribosome presumably to drive ribosome
CC nuclear export. Associated with nucleolar ribonucleoprotein
CC structures and bind single-stranded nucleic acids. Acts as a
CC chaperonin for the core histones H3, H2B and H4. Stimulates APEX1
CC endonuclease activity on apurinic/apyrimidinic (AP) double-
CC stranded DNA but inhibits APEX1 endonuclease activity on AP
CC single-stranded RNA. May exert a control of APEX1 endonuclease
CC activity within nucleoli devoted to repair AP on rDNA and the
CC removal of oxidized rRNA molecules. In concert with BRCA2,
CC regulates centrosome duplication. Regulates centriole duplication:
CC phosphorylation by PLK2 is able to trigger centriole replication.
CC Negatively regulates the activation of EIF2AK2/PKR and suppresses
CC apoptosis through inhibition of EIF2AK2/PKR autophosphorylation.
CC -!- SUBUNIT: Decamer formed by two pentameric rings associated in a
CC head-to-head fashion. Disulfide-linked dimers under certain
CC conditions. The SWAP complex consists of NPM1, NCL, PARP1 and
CC SWAP70 (By similarity). Interacts with NSUN2 and SENP3. Interacts
CC with hepatitis delta virus S-HDAg. Interacts with HTLV1 Rex
CC protein (via N-terminal nuclear localization signal). Interacts
CC with the methylated form of RPS10. Interacts (via N-terminal
CC domain) with APEX1; the interaction is RNA-dependent and decreases
CC in hydrogen peroxide-damaged cells. Interacts with isoform 1 of
CC NEK2. Interacts with ROCK2 and BRCA2. Interacts with RPGR.
CC Interacts with CENPW. Interacts with EIF2AK2/PKR.
CC -!- INTERACTION:
CC Q98147:- (xeno); NbExp=2; IntAct=EBI-78579, EBI-626601;
CC Q8N726:CDKN2A; NbExp=2; IntAct=EBI-78579, EBI-625922;
CC Q10570:CPSF1; NbExp=2; IntAct=EBI-78579, EBI-347859;
CC P19525:EIF2AK2; NbExp=3; IntAct=EBI-78579, EBI-640775;
CC Q9BZQ8:FAM129A; NbExp=7; IntAct=EBI-78579, EBI-6916466;
CC Q13547:HDAC1; NbExp=2; IntAct=EBI-78579, EBI-301834;
CC Q92769:HDAC2; NbExp=2; IntAct=EBI-78579, EBI-301821;
CC Q9BXL5:HEMGN; NbExp=7; IntAct=EBI-78579, EBI-3916399;
CC P24938:L2 (xeno); NbExp=4; IntAct=EBI-78579, EBI-7481199;
CC P68951:L2 (xeno); NbExp=5; IntAct=EBI-78579, EBI-7481182;
CC Q00987:MDM2; NbExp=5; IntAct=EBI-78579, EBI-389668;
CC Q8IZL8:PELP1; NbExp=3; IntAct=EBI-78579, EBI-716449;
CC Q9H4L4:SENP3; NbExp=6; IntAct=EBI-78579, EBI-2880236;
CC P05549:TFAP2A; NbExp=6; IntAct=EBI-78579, EBI-347351;
CC P04637:TP53; NbExp=6; IntAct=EBI-78579, EBI-366083;
CC P63104:YWHAZ; NbExp=2; IntAct=EBI-78579, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Nucleus, nucleolus. Nucleus, nucleoplasm.
CC Cytoplasm, cytoskeleton, microtubule organizing center,
CC centrosome. Note=Generally nucleolar, but is translocated to the
CC nucleoplasm in case of serum starvation or treatment with
CC anticancer drugs. Has been found in the cytoplasm in patients with
CC primary acute myelogenous leukemia (AML), but not with secondary
CC AML. Can shuttle between cytoplasm and nucleus. Co- localizes with
CC the methylated form of RPS10 in the granular component (GC) region
CC of the nucleolus. Colocalized with nucleolin and APEX1 in
CC nucleoli. Isoform 1 of NEK2 is required for its localization to
CC the centrosome during mitosis.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P06748-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P06748-2; Sequence=VSP_003616;
CC Name=3;
CC IsoId=P06748-3; Sequence=VSP_043599;
CC Note=Contains a N6-acetyllysine at position 257. Contains a
CC phosphoserine at position 254;
CC -!- PTM: Acetylated at C-terminal lysine residues, thereby increasing
CC affinity to histones.
CC -!- PTM: ADP-ribosylated.
CC -!- PTM: Phosphorylated at Ser-4 by PLK1 and PLK2. Phosphorylation at
CC Ser-4 by PLK2 in S phase is required for centriole duplication and
CC is sufficient to trigger centriole replication. Phosphorylation at
CC Ser-4 by PLK1 takes place during mitosis. Phosphorylated by CDK2
CC at Ser-125 and Thr-199. Phosphorylation at Thr-199 may trigger
CC initiation of centrosome duplication. Phosphorylated by CDK1 at
CC Thr-199, Thr-219, Thr-234 and Thr-237 during cell mitosis. When
CC these four sites are phosphorated, RNA-binding activity seem to be
CC abolished. May be phosphorylated at Ser-70 by NEK2. The Thr-199
CC phosphorylated form has higher affinity for ROCK2. CDK6 triggers
CC Thr-199 phosphorylation when complexed to Kaposi's sarcoma
CC herpesvirus (KSHV) V-cyclin, leading to viral reactivation by
CC reducing viral LANA levels.
CC -!- PTM: Sumoylated by ARF.
CC -!- DISEASE: Note=A chromosomal aberration involving NPM1 is found in
CC a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with
CC ALK. The resulting chimeric NPM1-ALK protein homodimerize and the
CC kinase becomes constitutively activated.
CC -!- DISEASE: Note=A chromosomal aberration involving NPM1 is found in
CC a form of acute promyelocytic leukemia. Translocation
CC t(5;17)(q32;q11) with RARA.
CC -!- DISEASE: Note=A chromosomal aberration involving NPM1 is a cause
CC of myelodysplastic syndrome (MDS). Translocation t(3;5)(q25.1;q34)
CC with MLF1.
CC -!- DISEASE: Note=Defects in NPM1 are associated with acute
CC myelogenous leukemia (AML). Mutations in exon 12 affecting the C-
CC terminus of the protein are associated with an aberrant
CC cytoplasmic location.
CC -!- SIMILARITY: Belongs to the nucleoplasmin family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/NPM1.html";
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DR EMBL; M23613; AAA36380.1; -; mRNA.
DR EMBL; M28699; AAA58386.1; -; mRNA.
DR EMBL; M26697; AAA36385.1; -; mRNA.
DR EMBL; U89321; AAB94739.1; -; Genomic_DNA.
DR EMBL; U89309; AAB94739.1; JOINED; Genomic_DNA.
DR EMBL; U89310; AAB94739.1; JOINED; Genomic_DNA.
DR EMBL; U89311; AAB94739.1; JOINED; Genomic_DNA.
DR EMBL; U89313; AAB94739.1; JOINED; Genomic_DNA.
DR EMBL; U89314; AAB94739.1; JOINED; Genomic_DNA.
DR EMBL; U89317; AAB94739.1; JOINED; Genomic_DNA.
DR EMBL; U89319; AAB94739.1; JOINED; Genomic_DNA.
DR EMBL; AB042278; BAB40600.1; -; mRNA.
DR EMBL; AY740634; AAW67752.1; -; mRNA.
DR EMBL; AY740635; AAW67753.1; -; mRNA.
DR EMBL; AY740636; AAW67754.1; -; mRNA.
DR EMBL; AY740637; AAW67755.1; -; mRNA.
DR EMBL; AY740638; AAW67756.1; -; mRNA.
DR EMBL; AY740639; AAW67757.1; -; mRNA.
DR EMBL; AY740640; AAW67758.1; -; mRNA.
DR EMBL; DQ303464; ABC40399.1; -; mRNA.
DR EMBL; AY347529; AAQ24860.1; -; mRNA.
DR EMBL; BT007011; AAP35657.1; -; mRNA.
DR EMBL; AK290652; BAF83341.1; -; mRNA.
DR EMBL; AB451236; BAG70050.1; -; mRNA.
DR EMBL; AB451361; BAG70175.1; -; mRNA.
DR EMBL; CH471062; EAW61443.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61446.1; -; Genomic_DNA.
DR EMBL; BC002398; AAH02398.1; -; mRNA.
DR EMBL; BC008495; AAH08495.1; -; mRNA.
DR EMBL; BC009623; AAH09623.1; -; mRNA.
DR EMBL; BC012566; AAH12566.1; -; mRNA.
DR EMBL; BC014349; AAH14349.1; -; mRNA.
DR EMBL; BC016716; AAH16716.1; -; mRNA.
DR EMBL; BC016768; AAH16768.1; -; mRNA.
DR EMBL; BC016824; AAH16824.1; -; mRNA.
DR EMBL; BC021668; AAH21668.1; -; mRNA.
DR EMBL; BC021983; AAH21983.1; -; mRNA.
DR EMBL; BC050628; AAH50628.1; -; mRNA.
DR EMBL; BC107754; AAI07755.1; -; mRNA.
DR EMBL; U41742; AAB00112.1; ALT_TERM; mRNA.
DR EMBL; U41743; AAB00113.1; ALT_TERM; mRNA.
DR EMBL; U04946; AAA58698.1; ALT_TERM; mRNA.
DR EMBL; D45915; BAA08343.1; ALT_TERM; mRNA.
DR EMBL; X16934; CAA34809.1; -; mRNA.
DR EMBL; J02590; AAA36473.1; -; mRNA.
DR EMBL; M31004; AAA36474.1; -; mRNA.
DR PIR; A33423; A32915.
DR PIR; I38491; I38491.
DR RefSeq; NP_001032827.1; NM_001037738.2.
DR RefSeq; NP_002511.1; NM_002520.6.
DR RefSeq; NP_954654.1; NM_199185.3.
DR UniGene; Hs.557550; -.
DR PDB; 2LLH; NMR; -; A=225-294.
DR PDB; 2P1B; X-ray; 2.75 A; A/B/C/D/E/F/G/H/I/J=9-122.
DR PDB; 2VXD; NMR; -; A=243-294.
DR PDBsum; 2LLH; -.
DR PDBsum; 2P1B; -.
DR PDBsum; 2VXD; -.
DR ProteinModelPortal; P06748; -.
DR SMR; P06748; 15-118, 225-294.
DR DIP; DIP-30932N; -.
DR IntAct; P06748; 86.
DR MINT; MINT-4938330; -.
DR BindingDB; P06748; -.
DR ChEMBL; CHEMBL5178; -.
DR PhosphoSite; P06748; -.
DR DMDM; 114762; -.
DR DOSAC-COBS-2DPAGE; P06748; -.
DR REPRODUCTION-2DPAGE; IPI00549248; -.
DR SWISS-2DPAGE; P06748; -.
DR PaxDb; P06748; -.
DR PRIDE; P06748; -.
DR DNASU; 4869; -.
DR Ensembl; ENST00000296930; ENSP00000296930; ENSG00000181163.
DR Ensembl; ENST00000351986; ENSP00000341168; ENSG00000181163.
DR Ensembl; ENST00000393820; ENSP00000377408; ENSG00000181163.
DR Ensembl; ENST00000517671; ENSP00000428755; ENSG00000181163.
DR GeneID; 4869; -.
DR KEGG; hsa:4869; -.
DR UCSC; uc003mbi.3; human.
DR CTD; 4869; -.
DR GeneCards; GC05P170814; -.
DR HGNC; HGNC:7910; NPM1.
DR HPA; CAB012983; -.
DR HPA; HPA011384; -.
DR MIM; 164040; gene.
DR neXtProt; NX_P06748; -.
DR Orphanet; 520; Acute promyelocytic leukemia.
DR PharmGKB; PA31712; -.
DR eggNOG; NOG79897; -.
DR HOGENOM; HOG000013061; -.
DR HOVERGEN; HBG001860; -.
DR InParanoid; P06748; -.
DR KO; K11276; -.
DR OMA; NCFRTED; -.
DR OrthoDB; EOG79W97G; -.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; NPM1; human.
DR EvolutionaryTrace; P06748; -.
DR GeneWiki; NPM1; -.
DR GenomeRNAi; 4869; -.
DR NextBio; 18752; -.
DR PMAP-CutDB; P06748; -.
DR PRO; PR:P06748; -.
DR ArrayExpress; P06748; -.
DR Bgee; P06748; -.
DR Genevestigator; P06748; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
DR GO; GO:0030529; C:ribonucleoprotein complex; IDA:MGI.
DR GO; GO:0031616; C:spindle pole centrosome; IDA:UniProtKB.
DR GO; GO:0042393; F:histone binding; IDA:UniProtKB.
DR GO; GO:0051059; F:NF-kappaB binding; IDA:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IMP:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0004860; F:protein kinase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0043023; F:ribosomal large subunit binding; IDA:MGI.
DR GO; GO:0043024; F:ribosomal small subunit binding; IDA:MGI.
DR GO; GO:0003723; F:RNA binding; IDA:UniProtKB.
DR GO; GO:0030957; F:Tat protein binding; IDA:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0051082; F:unfolded protein binding; IDA:UniProtKB.
DR GO; GO:0007569; P:cell aging; IMP:UniProtKB.
DR GO; GO:0034080; P:CENP-A containing nucleosome assembly at centromere; TAS:Reactome.
DR GO; GO:0007098; P:centrosome cycle; IMP:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IDA:UniProtKB.
DR GO; GO:0006886; P:intracellular protein transport; TAS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IMP:UniProtKB.
DR GO; GO:0010826; P:negative regulation of centrosome duplication; IMP:UniProtKB.
DR GO; GO:0044387; P:negative regulation of protein kinase activity by regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0006913; P:nucleocytoplasmic transport; IDA:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; IDA:UniProtKB.
DR GO; GO:0051259; P:protein oligomerization; IDA:MGI.
DR GO; GO:0046599; P:regulation of centriole replication; IMP:UniProtKB.
DR GO; GO:0060735; P:regulation of eIF2 alpha phosphorylation by dsRNA; IDA:UniProtKB.
DR GO; GO:0032071; P:regulation of endodeoxyribonuclease activity; IDA:UniProtKB.
DR GO; GO:0060699; P:regulation of endoribonuclease activity; IDA:UniProtKB.
DR GO; GO:0042255; P:ribosome assembly; TAS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR Gene3D; 2.60.120.340; -; 1.
DR InterPro; IPR004301; Nucleoplasmin.
DR InterPro; IPR024057; Nucleoplasmin_core_dom.
DR PANTHER; PTHR22747; PTHR22747; 1.
DR SUPFAM; SSF69203; SSF69203; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ADP-ribosylation; Alternative splicing;
KW Chaperone; Chromosomal rearrangement; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disulfide bond;
KW Host-virus interaction; Isopeptide bond; Nucleus; Phosphoprotein;
KW Proto-oncogene; Reference proteome; RNA-binding; Ubl conjugation.
FT CHAIN 1 294 Nucleophosmin.
FT /FTId=PRO_0000219481.
FT REGION 1 186 Required for interaction with SENP3.
FT REGION 1 117 Necessary for interaction with APEX1.
FT REGION 243 294 Required for nucleolar localization.
FT MOTIF 152 157 Nuclear localization signal (Potential).
FT MOTIF 191 197 Nuclear localization signal (Potential).
FT COMPBIAS 1 9 Met-rich.
FT COMPBIAS 120 132 Asp/Glu-rich (acidic).
FT COMPBIAS 161 188 Asp/Glu-rich (highly acidic).
FT SITE 55 55 Interaction between pentamers (By
FT similarity).
FT SITE 80 80 Interaction between pentamers (By
FT similarity).
FT SITE 175 176 Breakpoint for translocation to form
FT NPM1-MLF1.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 4 4 Phosphoserine; by PLK1 and PLK2.
FT MOD_RES 10 10 Phosphoserine.
FT MOD_RES 32 32 N6-acetyllysine.
FT MOD_RES 70 70 Phosphoserine.
FT MOD_RES 75 75 Phosphothreonine.
FT MOD_RES 95 95 Phosphothreonine.
FT MOD_RES 125 125 Phosphoserine; by CDK2.
FT MOD_RES 137 137 Phosphoserine.
FT MOD_RES 139 139 Phosphoserine.
FT MOD_RES 150 150 N6-acetyllysine.
FT MOD_RES 154 154 N6-acetyllysine.
FT MOD_RES 199 199 Phosphothreonine; by CDK1, CDK2 and CDK6.
FT MOD_RES 212 212 N6-acetyllysine.
FT MOD_RES 219 219 Phosphothreonine; by CDK1.
FT MOD_RES 227 227 Phosphoserine.
FT MOD_RES 229 229 N6-acetyllysine.
FT MOD_RES 230 230 N6-acetyllysine; alternate.
FT MOD_RES 234 234 Phosphothreonine; by CDK1.
FT MOD_RES 237 237 Phosphothreonine; by CDK1.
FT MOD_RES 242 242 Phosphoserine.
FT MOD_RES 243 243 Phosphoserine.
FT MOD_RES 250 250 N6-acetyllysine.
FT MOD_RES 254 254 Phosphoserine.
FT MOD_RES 257 257 N6-acetyllysine.
FT MOD_RES 260 260 Phosphoserine.
FT MOD_RES 267 267 N6-acetyllysine.
FT MOD_RES 273 273 N6-acetyllysine.
FT MOD_RES 279 279 Phosphothreonine.
FT MOD_RES 292 292 N6-acetyllysine.
FT CROSSLNK 230 230 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO);
FT alternate.
FT CROSSLNK 263 263 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT VAR_SEQ 195 223 Missing (in isoform 2).
FT /FTId=VSP_003616.
FT VAR_SEQ 258 294 GGSLPKVEAKFINYVKNCFRMTDQEAIQDLWQWRKSL ->
FT AH (in isoform 3).
FT /FTId=VSP_043599.
FT MUTAGEN 4 4 S->A: Abolishes phosphorylation by PLK2
FT and impairs centriole duplication.
FT MUTAGEN 4 4 S->D,E: Mimicks phosphorylation state,
FT inducing accumulation of centrioles.
FT MUTAGEN 95 95 T->A: Does not affect phosphorylation by
FT PLK2.
FT MUTAGEN 125 125 S->A: Does not affect phosphorylation by
FT PLK2.
FT MUTAGEN 199 199 T->A: Partial loss of phosphorylation.
FT Does not affect phosphorylation by PLK2.
FT MUTAGEN 219 219 T->A: Partial loss of phosphorylation.
FT MUTAGEN 234 234 T->A: Partial loss of phosphorylation;
FT when associated with A-237.
FT MUTAGEN 237 237 T->A: Partial loss of phosphorylation.
FT MUTAGEN 248 248 K->A: Partial destabilization of the
FT structure.
FT MUTAGEN 250 250 K->A: Increase in the stabilization of
FT the structure.
FT MUTAGEN 263 263 K->A: Increase in the stabilization of
FT the structure and partial delocalization
FT to the nucleoplasm. Complete
FT delocalization to the nucleoplasm; when
FT associated with A-267.
FT MUTAGEN 263 263 K->R: No change in the sumoylation level.
FT MUTAGEN 267 267 K->A: Increase in the stabilization of
FT the structure and complete delocalization
FT to the nucleoplasm. Complete
FT delocalization to the nucleoplasm; when
FT associated with A-263.
FT MUTAGEN 268 268 F->A: Complete destabilization of the
FT structure and loss of nucleolus
FT localization; when associated with A-276.
FT MUTAGEN 276 276 F->A: Complete destabilization of the
FT structure and loss of nucleolus
FT localization; when associated with A-268.
FT MUTAGEN 288 288 W->A: Complete destabilization of the
FT structure; when associated with A-290.
FT MUTAGEN 290 290 W->A: Partial destabilization of the
FT structure. Complete destabilization of
FT the structure; when associated with A-
FT 288.
FT CONFLICT 80 80 K -> E (in Ref. 13; AAH21983).
FT CONFLICT 129 129 E -> D (in Ref. 22; AA sequence).
FT CONFLICT 168 168 Missing (in Ref. 6; AAW67758).
FT CONFLICT 178 178 D -> G (in Ref. 13; AAH16768).
FT CONFLICT 183 183 D -> N (in Ref. 11; BAG70175/BAG70050).
FT CONFLICT 213 213 D -> P (in Ref. 23; AAA36473/AAA36474).
FT CONFLICT 214 214 S -> L (in Ref. 21; AA sequence).
FT CONFLICT 216 216 P -> S (in Ref. 23; AAA36473).
FT CONFLICT 219 221 TPR -> SSS (in Ref. 23; AAA36473).
FT CONFLICT 231 231 Q -> R (in Ref. 8; AAQ24860).
FT CONFLICT 271 271 Y -> C (in Ref. 13; AAH16768).
FT CONFLICT 287 287 L -> F (in Ref. 13; AAH12566).
FT CONFLICT 288 294 WQWRKSL -> CLAVEEVSLRK (in Ref. 6;
FT AAW67752/AAW67755).
FT CONFLICT 288 294 WQWRKSL -> CMAVEEVSLRK (in Ref. 6;
FT AAW67753 and 7; ABC40399).
FT CONFLICT 288 294 WQWRKSL -> CVAVEEVSLRK (in Ref. 6;
FT AAW67754).
FT CONFLICT 290 294 WRKSL -> SLAQVSLRK (in Ref. 6; AAW67756).
FT CONFLICT 290 294 WRKSL -> SLEKVSLRK (in Ref. 6; AAW67757).
FT STRAND 16 19
FT STRAND 29 31
FT STRAND 41 49
FT STRAND 58 65
FT STRAND 69 80
FT TURN 81 83
FT STRAND 84 94
FT STRAND 96 105
FT STRAND 109 116
FT HELIX 244 257
FT HELIX 265 275
FT HELIX 281 292
SQ SEQUENCE 294 AA; 32575 MW; 620BC7BA2E4A0054 CRC64;
MEDSMDMDMS PLRPQNYLFG CELKADKDYH FKVDNDENEH QLSLRTVSLG AGAKDELHIV
EAEAMNYEGS PIKVTLATLK MSVQPTVSLG GFEITPPVVL RLKCGSGPVH ISGQHLVAVE
EDAESEDEEE EDVKLLSISG KRSAPGGGSK VPQKKVKLAA DEDDDDDDEE DDDEDDDDDD
FDDEEAEEKA PVKKSIRDTP AKNAQKSNQN GKDSKPSSTP RSKGQESFKK QEKTPKTPKG
PSSVEDIKAK MQASIEKGGS LPKVEAKFIN YVKNCFRMTD QEAIQDLWQW RKSL
//

MIM 164040
*RECORD*
*FIELD* NO
164040
*FIELD* TI
*164040 NUCLEOPHOSMIN/NUCLEOPLASMIN FAMILY, MEMBER 1; NPM1
;;NUCLEOPHOSMIN; NPM;;
NUCLEOLAR PHOSPHOPROTEIN B23;;
read moreNUMATRIN
NPM1/ALK FUSION GENE, INCLUDED
*FIELD* TX

DESCRIPTION

NPM1 is a ubiquitously expressed nucleolar protein that shuttles between
the nucleus and cytoplasm. It is implicated in multiple functions,
including ribosomal protein assembly and transport, control of
centrosome duplication, and regulation of the tumor suppressor ARF
(600160). NPM1 mutations that relocalize NPM1 from the nucleus into the
cytoplasm are associated with development of acute myeloid leukemia
(AML; 601626) (Garzon et al., 2008).

CLONING

Chan et al. (1989) reported the nucleotide sequence of a cDNA of human
nucleophosmin. The cDNA has a coding sequence equivalent to a protein of
294 amino acids. When protein levels were compared with Western blot
immunoassays, Novikoff hepatoma showed 20 times more nucleophosmin than
normal, and hypertrophic rat liver showed about 5 times more
nucleophosmin than unstimulated normal liver.

Dalenc et al. (2002) developed a HeLa cell line that overexpressed FGF2
(134920) and showed radioresistance following exposure to ionizing
radiation. By differential display, they determined that the
radioresistant cells upregulated expression of an NPM1 splice variant.
This variant, which Dalenc et al. (2002) designated NPM2, encodes a
deduced 259-amino acid protein that differs from the original isolate
only at the C terminus. Western blot analysis of HeLa cells detected
both NPM isoforms, which migrated with apparent molecular masses of 38
and 34 kD. The amount of the shorter isoform increased following FGF2
overexpression.

GENE FUNCTION

Chan et al. (1989) found that nucleophosmin is a nucleolar
phosphoprotein that is more abundant in tumor cells than in normal
resting cells. Stimulation of the growth of normal cells, e.g., mitogen
activation of B lymphocytes, was accompanied by an increase in
nucleophosmin protein level. They stated that nucleophosmin is likely
involved in the assembly of ribosomal proteins into ribosomes. Electron
microscopic study indicated that nucleophosmin is concentrated in the
granular region of the nucleolus, where ribosome assembly occurs.

Okuda et al. (2000) identified nucleophosmin as a substrate of CDK2
(116953)/cyclin E (123837) in centrosome duplication. NPM1 associated
with unduplicated centrosomes, and dissociated from centrosomes by
CDK2/cyclin E-mediated phosphorylation. An anti-NPM1 antibody, which
blocked this phosphorylation, suppressed the initiation of centrosome
duplication in vivo. Moreover, expression of a nonphosphorylatable
mutant NPM1 in cells effectively blocked centrosome duplication. Okuda
et al. (2000) concluded that NPM1 is a target of CDK2/cyclin E in the
initiation of centrosome duplication.

By immunohistochemistry using antibodies that did not differentiate
between NPM1 isoforms, Dalenc et al. (2002) found nuclear staining for
NPM1 in control HeLa cells and cytoplasmic staining following
transfection with FGF2. They concluded that overexpression of FGF2
caused the redistribution of both NPM1 isoforms. By transfection of the
C-terminally truncated NPM1 variant (NPM2) into radiosensitive HeLa
cells, Dalenc et al. (2002) showed that the radioresistance associated
with FGF2 overexpression was mediated by increased expression of this
NPM1 isoform.

- NPM1/ALK Fusion Protein

Zhang et al. (2007) stated that ALK (105590) tyrosine kinase expression
is normally confined to neural cells, but chromosomal translocations
involving ALK and various partners, most frequently NPM1, result in
ectopic expression of ALK in a subset of T-cell lymphomas (TCLs) (see
CYTOGENETICS). The NPM1/ALK fusion protein contains the NPM1
oligomerization motif and the ALK catalytic domain, is constitutively
activated through autophosphorylation, and mediates malignant cell
transformation in vitro and in vivo by activating downstream effectors,
including STAT3 (102582). Zhang et al. (2007) found that TCL cell lines
expressing NPM1/ALK expressed STAT5B (604260), but not STAT5A (601511),
protein, whereas normal resting and activated T cells from peripheral
blood and ALK-negative TCL cell lines expressed STAT5A protein.
Activated NPM1/ALK-positive TCL cell lines also did not express STAT5A
mRNA, in spite of having an intact STAT5A gene. Analysis of the CpG
island in the STAT5A promoter showed that the region was methylated in
NPM1/ALK-positive, but not NPM1/ALK-negative, T cells. Chromatin
immunoprecipitation analysis revealed that SP1 (189906) bound the STAT5A
promoter in normal activated T cells, whereas MECP2 (300005) bound the
promoter of NPM1/ALK-positive TCL cells. Demethylation of the promoter
resulted in STAT5A activation and inhibition of NPM1/ALK expression by
binding of STAT5A to the NPM1/ALK fusion gene. Expression of NPM1/ALK in
NPM1/ALK-negative TCL cells resulted in silencing of STAT5A in a
STAT3-dependent manner, whereas small interfering RNA mediated-depletion
of NPM1/ALK resulted in STAT5A expression. Zhang et al. (2007) concluded
that NPM1/ALK induces epigenetic silencing of the STAT5A gene and that
the STAT5A protein can act as a tumor suppressor by inhibiting NPM1/ALK
expression.

BIOCHEMICAL FEATURES

Dutta et al. (2001) presented the structure of an N-terminal domain of
Xenopus nucleoplasmin (Np-core), which is related to NPM1, at
2.3-angstrom resolution. The Np-core monomer is an 8-stranded beta
barrel that fits snugly within a stable pentamer. In the crystal, 2
pentamers associate to form a decamer. The authors showed that both Np
and Np-core are competent to assemble large complexes that contain the 4
core histones. These complexes each contain 5 histone octamers that dock
to a central Np decamer. Dutta et al. (2001) provided models of histone
storage, sperm chromatin decondensation, and nucleosome assembly.

GENE STRUCTURE

Dalenc et al. (2002) stated that the NPM1 gene contains 12 exons.

MAPPING

The NPM1 gene maps to chromosome 5q35.

CYTOGENETICS

Large-cell lymphomas comprise approximately 25% of all non-Hodgkin
lymphomas in children and young adults. Approximately one-third of these
tumors have a t(2;5)(p23;q35) chromosomal translocation, which suggests
that rearrangement of cellular protooncogenes on these chromosomes
contributes to lymphomagenesis. To clone the genes altered by the
t(2;5), Morris et al. (1994) used a positional strategy based on
fluorescence in situ hybridization (FISH) ordering of regionally derived
cosmid clones. Bidirectional chromosome walks were performed from
cosmids approximately 290 kb apart that flanked the breakpoint on
chromosome 5; each walk spanned a genomic region of 150 kb. In this way,
they showed that the rearrangement fused the NPM nucleolar
phosphoprotein gene on 5q35 to a previously unidentified protein
tyrosine kinase gene, ALK (105590), on chromosome 2p23. In the predicted
hybrid protein, the N-terminus of nucleophosmin was found to be linked
to the catalytic domain of ALK. Expressed in the small intestine,
testis, and brain but not in normal lymphoid cells, ALK shows greatest
sequence similarity to the insulin receptor subfamily of kinases.
Unscheduled expression of the truncated ALK may contribute to malignant
transformation in these lymphomas. FISH mapping indicated that the NPM
and ALK genes are transcribed in centromere-to-telomere orientations on
chromosome 5 and 2, respectively, with the 2.4-kb transcript arising
from the derivative 5 translocated chromosome. Northern blot analysis
provided no evidence for expression of a reciprocal ALK-NPM chimeric
transcript.

Acute promyelocytic leukemia (APL; 612376) is uniquely associated with
chromosomal translocations that disrupt the gene encoding the retinoic
acid receptor, RARA (180240). In more than 99% of cases, this disruption
results from the formation of a PML-RARA fusion gene through
translocation. Rare variants of APL have been described, in which RARA
is fused to 1 of 3 other genes, PLZF (176797), NUMA (164009), and NPM
(Redner et al., 1996).

MOLECULAR GENETICS

NPM, a nucleocytoplasmic shuttling protein with prominent nucleolar
localization, regulates the ARF (103180)/p53 (191170) tumor suppressor
pathway. Chromosomal translocations involving the NPM gene cause
cytoplasmic dislocation of the NPM protein. Falini et al. (2005) used
immunohistochemical methods to study the subcellular localization of NPM
in bone marrow biopsy specimens from 591 patients with primary acute
myelogenous leukemia (AML; 601626). They then correlated the presence of
cytoplasmic NPM with clinical and biologic features of the disease.
Cytoplasmic NPM was detected in 35.2% of the 591 specimens from patients
with primary AML but not in 135 secondary AML specimens or in 980
hematopoietic or extrahematopoietic neoplasms other than AML. It was
associated with a wide spectrum of morphologic subtypes of the disease,
a normal karyotype, and responsiveness to induction chemotherapy, but
not with recurrent genetic abnormalities. There was a high frequency of
internal tandem duplications of FLT3 (136351) and absence of CD34
(142230) and CD133 (604365) in AML specimens with a normal karyotype and
cytoplasmic dislocation of NPM, but not in those in which the protein
was restricted to the nucleus. AML specimens with cytoplasmic NPM
carried mutations in the NPM gene (see 164040.0001-164040.0004); this
mutant gene caused cytoplasmic localization of NPM in transfected cells.
All 6 NPM mutant proteins showed mutations in at least 1 of the
tryptophan residues at positions 288 and 290 and shared the same last 5
amino acid residues (VSLRK). Thus, despite genetic heterogeneity, all
NPM gene mutations resulted in a distinct sequence in the NPM protein C
terminus. Falini et al. (2005) concluded that cytoplasmic NPM is a
characteristic feature of a large subgroup of patients with AML who have
a normal karyotype, NPM gene mutations, and responsiveness to induction
chemotherapy. Grisendi and Pandolfi (2005) noted that NPM staining in
cases of AML with aberrant cytoplasmic localization of the protein is
mostly cytoplasmic, which suggests that the mutant NPM acts dominantly
on the product of the remaining wildtype allele, causing its retention
in the cytoplasm by heterodimerization.

By microRNA (miRNA) expression profiling, Garzon et al. (2008)
identified 36 upregulated and 21 downregulated miRNAs in AML patients
with NPM1 mutations compared with AML patients without NPM1 mutations.
miR10A (MIRN10A; 610173) and miR10B (MIRN10B; 611576) showed the
greatest upregulation, with increases of 20- and 16.67-fold,
respectively. Mir22 (MIRN22; 612077) showed greatest downregulation,
with a reduction of 0.31-fold. Garzon et al. (2008) concluded that AML
with NPM1 mutations has a distinctive miRNA signature.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. The authors identified recurrent mutations in the NPM1 gene in
54 of 200 (27%) samples.

Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that genes mutated almost exclusively in
founding clones in their study included NPM1 (3 of 3 mutations in
founding clones). They identified several other genes that contained
mutations they considered probable initiators, and other genes in which
mutations were considered probably cooperating mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

Gale et al. (2008) found that 354 (26%) of 1,425 patients with AML had
the FLT3 internal duplication. The median total mutant level for all
patients was 35% of total FLT3, but there was wide variation with levels
ranging from 1 to 96%. There was a significant correlation between worse
overall survival, relapse risk, and increased white blood cell count
with increased mutant level, but the size of the duplication and the
number of mutations had no significant impact on outcome. Those patients
with the FLT3 duplication had a worse risk of relapse than patients
without the FLT3 duplication. Among a subset of 1,217 patients, 503
(41%) had a mutation in the NPM1 gene (164040), and 208 (17%) had
mutations in both genes. The presence of an NPM1 mutation had a
beneficial effect on the remission rate, most likely due to a lower rate
of resistant disease, both in patients with and without FLT3
duplications. Gale et al. (2008) identified 3 prognostic groups among
AML patients: good in those with only a NPM1 mutation; intermediate in
those with either no FLT3 or NPM1 mutations or mutations in both genes;
and poor in those with only FLT3 mutations.

ANIMAL MODEL

Cheng et al. (1999) generated transgenic mice with Plzf-Rara and
Npm-Rara. Plzf-Rara transgenic animals developed chronic myeloid
leukemia-like phenotypes at an early stage in life (within 3 months in 5
of 6 mice), whereas 3 Npm-Rara transgenic mice showed a spectrum of
phenotypes from typical APL to chronic myeloid leukemia relatively late
in life (from 12 to 15 months). In contrast to bone marrow cells from
Plzf-Rara transgenic mice, those from Npm-Rara transgenic mice could be
induced to differentiate by all-trans-retinoic acid (ATRA). Cheng et al.
(1999) found that in interacting with nuclear coreceptors the 2 fusion
proteins had different ligand sensitivities, which may be the underlying
molecular mechanism for differential responses to ATRA. These data
clearly established the leukemogenic role of PLZF-RARA and NPM-RARA and
the importance of fusion receptor/corepressor interactions in the
pathogenesis as well as in determining different clinical phenotypes of
APL.

To study the function of Npm in vivo, Grisendi et al. (2005) generated a
hypomorphic Npm1 mutant series comprising Npm1 heterozygous-null,
hypomorphic mutant, and homozygous-null mice. They observed that Npm1
homozygous-null and hypomorphic mutants had aberrant organogenesis and
died between embryonic days 11.5 and 16.5 owing to severe anemia
resulting from defects in primitive hematopoiesis. Grisendi et al.
(2005) showed that Npm1 inactivation leads to unrestricted centrosome
duplication and genomic instability. Grisendi et al. (2005) demonstrated
that Npm is haploinsufficient in the control of genetic stability and
that Npm1 heterozygosity accelerates oncogenesis both in vitro and in
vivo. Notably, Npm1 heterozygous mice developed a hematologic syndrome
with features of human myelodysplastic syndrome (MDS). Grisendi et al.
(2005) concluded that their data uncovered an essential developmental
role for Npm and implicated its functional loss in tumorigenesis and MDS
pathogenesis.

*FIELD* AV
.0001
LEUKEMIA, ACUTE MYELOID
NPM1, 4-BP DUP, 956TCTG

In 40 of 51 cases of acute myeloid leukemia (601626) with positivity for
NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp duplication
in exon 12 of the NPM1 gene (956dupTCTG), resulting in a shift in the
reading frame that was predicted to alter the C-terminal portion of the
protein by replacing the last 7 amino acids with 11 different residues.
Falini et al. (2005) called this mutation, which was the most frequent
of those identified, mutation A.

.0002
LEUKEMIA, ACUTE MYELOID
NPM1, 4-BP INS, 960CATG

In 7 of 51 cases of acute myeloid leukemia (601626) with positivity for
NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp insertion
in exon 12 of the NPM1 gene (960insCATG), resulting in a shift in the
reading frame that was predicted to alter the C-terminal portion of the
protein by replacing the last 7 amino acids with 11 different residues.
Falini et al. (2005) called this mutation B.

.0003
LEUKEMIA, ACUTE MYELOID
NPM1, 4-BP INS, 960CGTG

In 1 of 51 cases of acute myeloid leukemia (601626) with positivity for
NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp insertion
in exon 12 of the NPM1 gene (960insCGTG), resulting in a shift in the
reading frame that was predicted to alter the C-terminal portion of the
protein by replacing the last 7 amino acids with 11 different residues.
Falini et al. (2005) called this mutation C.

.0004
LEUKEMIA, ACUTE MYELOID
NPM1, 4-BP INS, 960CCTG

In 1 of 51 cases of acute myeloid leukemia (601626) with positivity for
NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp insertion
in exon 12 of the NPM1 gene (960insCCTG), resulting in a shift in the
reading frame that was predicted to alter the C-terminal portion of the
protein by replacing the last 7 amino acids with 11 different residues.
Falini et al. (2005) called this mutation D.

*FIELD* RF
1. Brewin, J.; Horne, G.; Chevassut, T.: Genomic landscapes and clonality
of de novo AML. (Letter) New Eng. J. Med. 369: 1472-1473, 2013.

2. Cancer Genome Atlas Research Network: Genomic and epigenomic
landscapes of adult de novo acute myeloid leukemia. New Eng. J. Med. 368:
2059-2074, 2013. Note: Erratum: New Eng. J. Med. 369: 98 only, 2013.

3. Chan, W.-Y.; Liu, Q.-R.; Borjigin, J.; Busch, H.; Rennert, O. M.;
Tease, L. A.; Chan, P.-K.: Characterization of the cDNA encoding
human nucleophosmin and studies of its role in normal and abnormal
growth. Biochemistry 28: 1033-1039, 1989.

4. Cheng, G.-X.; Zhu, X.-H.; Men, X.-Q.; Wang, L.; Huang, Q.-H.; Jin,
X. L.; Xiong, S.-M.; Zhu, J.; Guo, W.-M.; Chen, J.-Q.; Xu, S.-F.;
So, E.; Chan, L.-C.; Waxman, S.; Zelent, A.; Chen, G.-Q.; Dong, S.;
Liu, J.-X.; Chen, S.-J.: Distinct leukemia phenotypes in transgenic
mice and different corepressor interactions generated by promyelocytic
leukemia variant fusion genes PLZF-RAR-alpha and NPM-RAR-alpha. Proc.
Nat. Acad. Sci. 96: 6318-6323, 1999.

5. Dalenc, F.; Drouet, J.; Ader, I.; Delmas, C.; Rochaix, P.; Favre,
G.; Cohen-Jonathan, E.; Toulas, C.: Increased expression of a COOH-truncated
nucleophosmin resulting from alternative splicing is associated with
cellular resistance to ionizing radiation in HeLa cells. Int. J.
Cancer 100: 662-668, 2002.

6. Dutta, S.; Akey, I. V.; Dingwall, C.; Hartman, K. L.; Laue, T.;
Nolte, R. T.; Head, J. F.; Akey, C. W.: The crystal structure of
nucleoplasmin-core: implications for histone binding and nucleosome
assembly. Molec. Cell 8: 841-853, 2001.

7. Falini, B.; Mecucci, C.; Tiacci, E.; Alcalay, M.; Rosati, R.; Pasqualucci,
L.; La Starza, R.; Diverio, D.; Colombo, E.; Santucci, A.; Bigerna,
B.; Pacini, R.; and 11 others: Cytoplasmic nucleophosmin in acute
myelogenous leukemia with a normal karyotype. New Eng. J. Med. 352:
254-266, 2005. Note: Erratum: New Eng. J. Med. 352: 740 only, 2005.

8. Gale, R. E.; Green, C.; Allen, C.; Mead, A. J.; Burnett, A. K.;
Hills, R. K.; Linch, D. C.: The impact of FLT3 tandem duplication
mutant level, number, size, and interaction with NPM1 mutations in
a large cohort of young adult patients with acute myeloid leukemia. Blood 111:
2776-2784, 2008.

9. Garzon, R.; Garofalo, M.; Martelli, M. P.; Briesewitz, R.; Wang,
L.; Fernandez-Cymering, C.; Volinia, S.; Liu, C.-G.; Schnittger, S.;
Haferlach, T.; Liso, A.; Diverio, D.; Mancini, M.; Meloni, G.; Foa,
R.; Martelli, M. F.; Mecucci, C.; Croce, C. M.; Falini, B.: Distinctive
microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated
nucleophosmin. Proc. Nat. Acad. Sci. 105: 3945-3950, 2008.

10. Grisendi, S.; Bernardi, R.; Rossi, M.; Cheng, K.; Khandker, L.;
Manova, K.; Pandolfi, P. P.: Role of nucleophosmin in embryonic development
and tumorigenesis. Nature 437: 147-153, 2005.

11. Grisendi, S.; Pandolfi, P. P.: NPM mutations in acute myelogenous
leukemia. (Editorial) New Eng. J. Med. 352: 291-292, 2005.

12. Miller, C. A.; Wilson, R. K.; Ley, T. J.: Reply to Brewin et
al. (Letter) New Eng. J. Med. 369: 1473 only, 2013.

13. Morris, S. W.; Kirstein, M. N.; Valentine, M. B.; Dittmer, K.
G.; Shapiro, D. N.; Saltman, D. L.; Look, A. T.: Fusion of a kinase
gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263:
1281-1284, 1994. Note: Erratum: Science 267: 316-317, 1995.

14. Okuda, M.; Horn, H. F.; Tarapore, P.; Tokuyama, Y.; Smulian, A.
G.; Chan, P.-K.; Knudsen, E. S.; Hofmann, I. A.; Snyder, J. D.; Bove,
K. E.; Fukasawa, K.: Nucleophosmin/B23 is a target of CDK2/cyclin
E in centrosome duplication. Cell 103: 127-140, 2000.

15. Redner, R. L.; Rush, E. A.; Faas, S.; Rudert, W. A.; Corey, S.
J.: The t(5;17) variant of acute promyelocytic leukemia expresses
a nucleophosmin-retinoic acid receptor fusion. Blood 87: 882-886,
1996.

16. Zhang, Q.; Wang, H. Y.; Liu, X.; Wasik, M. A.: STAT5A is epigenetically
silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor
by reciprocally inhibiting NPM1-ALK expression. Nature Med. 13:
1341-1348, 2007.

*FIELD* CN
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Cassandra L. Kniffin - updated: 7/30/2008
Patricia A. Hartz - updated: 5/29/2008
Paul J. Converse - updated: 2/4/2008
Ada Hamosh - updated: 10/12/2005
Victor A. McKusick - updated: 1/31/2005
Patricia A. Hartz - updated: 9/3/2003
Stylianos E. Antonarakis - updated: 11/13/2001
Stylianos E. Antonarakis - updated: 10/19/2000
Victor A. McKusick - updated: 7/19/1999

*FIELD* CD
Victor A. McKusick: 3/23/1989

*FIELD* ED
carol: 12/03/2013
alopez: 11/25/2013
alopez: 7/9/2013
carol: 10/16/2012
mgross: 10/28/2008
wwang: 8/1/2008
ckniffin: 7/30/2008
mgross: 6/9/2008
terry: 5/29/2008
wwang: 5/22/2008
terry: 5/19/2008
mgross: 2/4/2008
alopez: 4/24/2006
alopez: 10/12/2005
carol: 4/22/2005
tkritzer: 2/7/2005
terry: 1/31/2005
tkritzer: 11/20/2003
mgross: 9/3/2003
mgross: 11/14/2001
mgross: 11/13/2001
mcapotos: 10/20/2000
mcapotos: 10/19/2000
terry: 10/19/2000
mgross: 7/19/1999
jenny: 9/3/1997
terry: 8/29/1997
terry: 6/22/1994
jason: 6/21/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 3/28/1989