Full text data of BMI1
BMI1
(PCGF4, RNF51)
[Confidence: low (only semi-automatic identification from reviews)]
Polycomb complex protein BMI-1 (Polycomb group RING finger protein 4; RING finger protein 51)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Polycomb complex protein BMI-1 (Polycomb group RING finger protein 4; RING finger protein 51)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P35226
ID BMI1_HUMAN Reviewed; 326 AA.
AC P35226; Q16030; Q5T8Z3; Q96F37;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-AUG-2002, sequence version 2.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Polycomb complex protein BMI-1;
DE AltName: Full=Polycomb group RING finger protein 4;
DE AltName: Full=RING finger protein 51;
GN Name=BMI1; Synonyms=PCGF4, RNF51;
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].
RC TISSUE=Erythrocyte;
RX PubMed=8268912; DOI=10.1093/hmg/2.10.1597;
RA Alkema M.J., Wiegand J., Raap A.K., Berns A., van Lohuizen M.;
RT "Characterization and chromosomal localization of the human proto-
RT oncogene BMI-1.";
RL Hum. Mol. Genet. 2:1597-1603(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 12-300.
RC TISSUE=Thymus;
RX PubMed=8390036;
RA Levy L.S., Lobelle-Rich P.A., Overbaugh J.;
RT "flvi-2, a target of retroviral insertional mutagenesis in feline
RT thymic lymphosarcomas, encodes bmi-1.";
RL Oncogene 8:1833-1838(1993).
RN [7]
RP INTERACTION WITH PHC2.
RX PubMed=9121482;
RA Gunster M.J., Satijn D.P.E., Hamer K.M., den Blaauwen J.L.,
RA de Bruijn D., Alkema M.J., van Lohuizen M., van Driel R., Otte A.P.;
RT "Identification and characterization of interactions between the
RT vertebrate polycomb-group protein BMI1 and human homologs of
RT polyhomeotic.";
RL Mol. Cell. Biol. 17:2326-2335(1997).
RN [8]
RP INTERACTION WITH PHC2.
RX PubMed=9199346;
RA Satijn D.P.E., Gunster M.J., van der Vlag J., Hamer K.M., Schul W.,
RA Alkema M.J., Saurin A.J., Freemont P.S., van Driel R., Otte A.P.;
RT "RING1 is associated with the polycomb group protein complex and acts
RT as a transcriptional repressor.";
RL Mol. Cell. Biol. 17:4105-4113(1997).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND IDENTIFICATION IN A PRC1-LIKE
RP HPRC-H COMPLEX WITH CBX2; CBX4; CBX8; PHC1; PHC2; PHC3; RING1 AND
RP RNF2.
RX PubMed=12167701; DOI=10.1128/MCB.22.17.6070-6078.2002;
RA Levine S.S., Weiss A., Erdjument-Bromage H., Shao Z., Tempst P.,
RA Kingston R.E.;
RT "The core of the polycomb repressive complex is compositionally and
RT functionally conserved in flies and humans.";
RL Mol. Cell. Biol. 22:6070-6078(2002).
RN [10]
RP IDENTIFICATION IN A PRC1-LIKE COMPLEX.
RX PubMed=15386022; DOI=10.1038/nature02985;
RA Wang H., Wang L., Erdjument-Bromage H., Vidal M., Tempst P.,
RA Jones R.S., Zhang Y.;
RT "Role of histone H2A ubiquitination in Polycomb silencing.";
RL Nature 431:873-878(2004).
RN [11]
RP FUNCTION.
RX PubMed=16359901; DOI=10.1016/j.molcel.2005.12.002;
RA Cao R., Tsukada Y., Zhang Y.;
RT "Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene
RT silencing.";
RL Mol. Cell 20:845-854(2005).
RN [12]
RP INTERACTION WITH SPOP, IDENTIFICATION IN A COMPLEX WITH CUL3 AND SPOP,
RP AND UBIQUITINATION.
RX PubMed=15897469; DOI=10.1073/pnas.0408918102;
RA Hernandez-Munoz I., Lund A.H., van der Stoop P., Boutsma E.,
RA Muijrers I., Verhoeven E., Nusinow D.A., Panning B., Marahrens Y.,
RA van Lohuizen M.;
RT "Stable X chromosome inactivation involves the PRC1 Polycomb complex
RT and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3
RT ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:7635-7640(2005).
RN [13]
RP FUNCTION, INTERACTION WITH E4F1, AND SUBCELLULAR LOCATION.
RX PubMed=16882984; DOI=10.1101/gad.1453406;
RA Chagraoui J., Niessen S.L., Lessard J., Girard S., Coulombe P.,
RA Sauvageau M., Meloche S., Sauvageau G.;
RT "E4F1: a novel candidate factor for mediating BMI1 function in
RT primitive hematopoietic cells.";
RL Genes Dev. 20:2110-2120(2006).
RN [14]
RP IDENTIFICATION IN A PRC1-LIKE COMPLEX, AND INTERACTION WITH CBX7 AND
RP CBX8.
RX PubMed=19636380; DOI=10.1371/journal.pone.0006380;
RA Maertens G.N., El Messaoudi-Aubert S., Racek T., Stock J.K.,
RA Nicholls J., Rodriguez-Niedenfuhr M., Gil J., Peters G.;
RT "Several distinct polycomb complexes regulate and co-localize on the
RT INK4a tumor suppressor locus.";
RL PLoS ONE 4:E6380-E6380(2009).
RN [15]
RP IDENTIFICATION IN A PRC1-LIKE COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=21282530; DOI=10.1074/mcp.M110.002642;
RA Vandamme J., Volkel P., Rosnoblet C., Le Faou P., Angrand P.O.;
RT "Interaction proteomics analysis of polycomb proteins defines distinct
RT PRC1 Complexes in mammalian cells.";
RL Mol. Cell. Proteomics 0:0-0(2011).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 5-101 IN COMPLEX WITH RNF2
RP AND ZINC IONS, FUNCTION, MASS SPECTROMETRY, AND SUBUNIT.
RX PubMed=16714294; DOI=10.1074/jbc.M602461200;
RA Li Z., Cao R., Wang M., Myers M.P., Zhang Y., Xu R.M.;
RT "Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase
RT complex.";
RL J. Biol. Chem. 281:20643-20649(2006).
CC -!- FUNCTION: Component of a Polycomb group (PcG) multiprotein PRC1-
CC like complex, a complex class required to maintain the
CC transcriptionally repressive state of many genes, including Hox
CC genes, throughout development. PcG PRC1 complex acts via chromatin
CC remodeling and modification of histones; it mediates
CC monoubiquitination of histone H2A 'Lys-119', rendering chromatin
CC heritably changed in its expressibility. In the PRC1 complex, it
CC is required to stimulate the E3 ubiquitin-protein ligase activity
CC of RNF2/RING2.
CC -!- SUBUNIT: Component of a PRC1-like complex. Interacts with RING1
CC and RING2 (By similarity). Interacts vwith CBX7 and CBX8.
CC Interacts with SPOP. Part of a complex consisting of BMI1, CUL3
CC and SPOP. Interacts with E4F1.
CC -!- INTERACTION:
CC O00257:CBX4; NbExp=4; IntAct=EBI-2341576, EBI-722425;
CC O00257-3:CBX4; NbExp=2; IntAct=EBI-2341576, EBI-4392727;
CC O95503:CBX6; NbExp=3; IntAct=EBI-2341576, EBI-3951758;
CC O95931:CBX7; NbExp=7; IntAct=EBI-2341576, EBI-3923843;
CC Q9HC52:CBX8; NbExp=13; IntAct=EBI-2341576, EBI-712912;
CC P60484:PTEN; NbExp=3; IntAct=EBI-2341576, EBI-696162;
CC Q06587:RING1; NbExp=11; IntAct=EBI-2341576, EBI-752313;
CC Q99496:RNF2; NbExp=9; IntAct=EBI-2341576, EBI-722416;
CC P0CG48:UBC; NbExp=2; IntAct=EBI-2341576, EBI-3390054;
CC P51784:USP11; NbExp=7; IntAct=EBI-2341576, EBI-306876;
CC Q93009:USP7; NbExp=7; IntAct=EBI-2341576, EBI-302474;
CC Q9H270:VPS11; NbExp=2; IntAct=EBI-2341576, EBI-373380;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm.
CC -!- PTM: Monoubiquitinated (By similarity). May be polyubiquitinated;
CC which does not lead to proteasomal degradation.
CC -!- MISCELLANEOUS: The hPRC-H complex purification reported by
CC PubMed:12167701 probably presents a mixture of different PRC1-like
CC complexes.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/BMI1ID807ch10p12.html";
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DR EMBL; L13689; AAA19873.1; -; mRNA.
DR EMBL; AK313235; BAG36046.1; -; mRNA.
DR EMBL; AL158211; CAI15958.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86148.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86150.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86151.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86154.1; -; Genomic_DNA.
DR EMBL; BC011652; AAH11652.1; -; mRNA.
DR EMBL; AH004292; AAB27059.1; -; mRNA.
DR PIR; I54339; I54339.
DR RefSeq; NP_001190991.1; NM_001204062.1.
DR RefSeq; NP_005171.4; NM_005180.8.
DR RefSeq; XP_005252619.1; XM_005252562.1.
DR RefSeq; XP_005252620.1; XM_005252563.1.
DR UniGene; Hs.380403; -.
DR UniGene; Hs.731287; -.
DR PDB; 2H0D; X-ray; 2.50 A; A=5-101.
DR PDB; 3RPG; X-ray; 2.65 A; B=1-109.
DR PDBsum; 2H0D; -.
DR PDBsum; 3RPG; -.
DR ProteinModelPortal; P35226; -.
DR SMR; P35226; 6-103.
DR DIP; DIP-41879N; -.
DR IntAct; P35226; 35.
DR MINT; MINT-158260; -.
DR STRING; 9606.ENSP00000365851; -.
DR PhosphoSite; P35226; -.
DR DMDM; 22258801; -.
DR PaxDb; P35226; -.
DR PRIDE; P35226; -.
DR DNASU; 648; -.
DR Ensembl; ENST00000376663; ENSP00000365851; ENSG00000168283.
DR GeneID; 100532731; -.
DR GeneID; 648; -.
DR KEGG; hsa:100532731; -.
DR KEGG; hsa:648; -.
DR UCSC; uc001irh.3; human.
DR CTD; 100532731; -.
DR CTD; 648; -.
DR GeneCards; GC10P022605; -.
DR HGNC; HGNC:1066; BMI1.
DR HPA; CAB011120; -.
DR HPA; HPA030472; -.
DR MIM; 164831; gene.
DR neXtProt; NX_P35226; -.
DR PharmGKB; PA25376; -.
DR eggNOG; NOG304672; -.
DR HOGENOM; HOG000231945; -.
DR HOVERGEN; HBG052826; -.
DR InParanoid; P35226; -.
DR KO; K11459; -.
DR OMA; RVRPNCK; -.
DR PhylomeDB; P35226; -.
DR Reactome; REACT_120956; Cellular responses to stress.
DR EvolutionaryTrace; P35226; -.
DR GeneWiki; BMI1; -.
DR NextBio; 2628; -.
DR PRO; PR:P35226; -.
DR ArrayExpress; P35226; -.
DR Bgee; P35226; -.
DR CleanEx; HS_BMI1; -.
DR Genevestigator; P35226; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0035102; C:PRC1 complex; IDA:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0016568; P:chromatin modification; IEA:UniProtKB-KW.
DR GO; GO:0030097; P:hemopoiesis; IEP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IMP:UniProtKB.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IMP:BHF-UCL.
DR GO; GO:0051443; P:positive regulation of ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0007379; P:segment specification; TAS:ProtInc.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR018957; Znf_C3HC4_RING-type.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR Pfam; PF00097; zf-C3HC4; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chromatin regulator; Complete proteome; Cytoplasm;
KW Metal-binding; Nucleus; Polymorphism; Proto-oncogene;
KW Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1 326 Polycomb complex protein BMI-1.
FT /FTId=PRO_0000055987.
FT ZN_FING 18 57 RING-type.
FT REGION 164 228 Interaction with E4F1.
FT MOTIF 81 95 Nuclear localization signal (Potential).
FT COMPBIAS 251 326 Pro/Ser-rich.
FT VARIANT 18 18 C -> Y (in dbSNP:rs1042059).
FT /FTId=VAR_052087.
FT CONFLICT 109 109 G -> S (in Ref. 6; AAB27059).
FT CONFLICT 265 265 I -> V (in Ref. 1; AAA19873).
FT STRAND 6 8
FT HELIX 9 12
FT HELIX 13 15
FT TURN 19 21
FT STRAND 22 24
FT STRAND 29 31
FT TURN 32 34
FT HELIX 40 46
FT TURN 54 56
FT HELIX 65 68
FT STRAND 69 71
FT HELIX 73 82
FT HELIX 86 100
SQ SEQUENCE 326 AA; 36949 MW; 030A7D396BADA543 CRC64;
MHRTTRIKIT ELNPHLMCVL CGGYFIDATT IIECLHSFCK TCIVRYLETS KYCPICDVQV
HKTRPLLNIR SDKTLQDIVY KLVPGLFKNE MKRRRDFYAA HPSADAANGS NEDRGEVADE
DKRIITDDEI ISLSIEFFDQ NRLDRKVNKD KEKSKEEVND KRYLRCPAAM TVMHLRKFLR
SKMDIPNTFQ IDVMYEEEPL KDYYTLMDIA YIYTWRRNGP LPLKYRVRPT CKRMKISHQR
DGLTNAGELE SDSGSDKANS PAGGIPSTSS CLPSPSTPVQ SPHPQFPHIS STMNGTSNSP
SGNHQSSFAN RPRKSSVNGS SATSSG
//
ID BMI1_HUMAN Reviewed; 326 AA.
AC P35226; Q16030; Q5T8Z3; Q96F37;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-AUG-2002, sequence version 2.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Polycomb complex protein BMI-1;
DE AltName: Full=Polycomb group RING finger protein 4;
DE AltName: Full=RING finger protein 51;
GN Name=BMI1; Synonyms=PCGF4, RNF51;
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].
RC TISSUE=Erythrocyte;
RX PubMed=8268912; DOI=10.1093/hmg/2.10.1597;
RA Alkema M.J., Wiegand J., Raap A.K., Berns A., van Lohuizen M.;
RT "Characterization and chromosomal localization of the human proto-
RT oncogene BMI-1.";
RL Hum. Mol. Genet. 2:1597-1603(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 12-300.
RC TISSUE=Thymus;
RX PubMed=8390036;
RA Levy L.S., Lobelle-Rich P.A., Overbaugh J.;
RT "flvi-2, a target of retroviral insertional mutagenesis in feline
RT thymic lymphosarcomas, encodes bmi-1.";
RL Oncogene 8:1833-1838(1993).
RN [7]
RP INTERACTION WITH PHC2.
RX PubMed=9121482;
RA Gunster M.J., Satijn D.P.E., Hamer K.M., den Blaauwen J.L.,
RA de Bruijn D., Alkema M.J., van Lohuizen M., van Driel R., Otte A.P.;
RT "Identification and characterization of interactions between the
RT vertebrate polycomb-group protein BMI1 and human homologs of
RT polyhomeotic.";
RL Mol. Cell. Biol. 17:2326-2335(1997).
RN [8]
RP INTERACTION WITH PHC2.
RX PubMed=9199346;
RA Satijn D.P.E., Gunster M.J., van der Vlag J., Hamer K.M., Schul W.,
RA Alkema M.J., Saurin A.J., Freemont P.S., van Driel R., Otte A.P.;
RT "RING1 is associated with the polycomb group protein complex and acts
RT as a transcriptional repressor.";
RL Mol. Cell. Biol. 17:4105-4113(1997).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND IDENTIFICATION IN A PRC1-LIKE
RP HPRC-H COMPLEX WITH CBX2; CBX4; CBX8; PHC1; PHC2; PHC3; RING1 AND
RP RNF2.
RX PubMed=12167701; DOI=10.1128/MCB.22.17.6070-6078.2002;
RA Levine S.S., Weiss A., Erdjument-Bromage H., Shao Z., Tempst P.,
RA Kingston R.E.;
RT "The core of the polycomb repressive complex is compositionally and
RT functionally conserved in flies and humans.";
RL Mol. Cell. Biol. 22:6070-6078(2002).
RN [10]
RP IDENTIFICATION IN A PRC1-LIKE COMPLEX.
RX PubMed=15386022; DOI=10.1038/nature02985;
RA Wang H., Wang L., Erdjument-Bromage H., Vidal M., Tempst P.,
RA Jones R.S., Zhang Y.;
RT "Role of histone H2A ubiquitination in Polycomb silencing.";
RL Nature 431:873-878(2004).
RN [11]
RP FUNCTION.
RX PubMed=16359901; DOI=10.1016/j.molcel.2005.12.002;
RA Cao R., Tsukada Y., Zhang Y.;
RT "Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene
RT silencing.";
RL Mol. Cell 20:845-854(2005).
RN [12]
RP INTERACTION WITH SPOP, IDENTIFICATION IN A COMPLEX WITH CUL3 AND SPOP,
RP AND UBIQUITINATION.
RX PubMed=15897469; DOI=10.1073/pnas.0408918102;
RA Hernandez-Munoz I., Lund A.H., van der Stoop P., Boutsma E.,
RA Muijrers I., Verhoeven E., Nusinow D.A., Panning B., Marahrens Y.,
RA van Lohuizen M.;
RT "Stable X chromosome inactivation involves the PRC1 Polycomb complex
RT and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3
RT ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:7635-7640(2005).
RN [13]
RP FUNCTION, INTERACTION WITH E4F1, AND SUBCELLULAR LOCATION.
RX PubMed=16882984; DOI=10.1101/gad.1453406;
RA Chagraoui J., Niessen S.L., Lessard J., Girard S., Coulombe P.,
RA Sauvageau M., Meloche S., Sauvageau G.;
RT "E4F1: a novel candidate factor for mediating BMI1 function in
RT primitive hematopoietic cells.";
RL Genes Dev. 20:2110-2120(2006).
RN [14]
RP IDENTIFICATION IN A PRC1-LIKE COMPLEX, AND INTERACTION WITH CBX7 AND
RP CBX8.
RX PubMed=19636380; DOI=10.1371/journal.pone.0006380;
RA Maertens G.N., El Messaoudi-Aubert S., Racek T., Stock J.K.,
RA Nicholls J., Rodriguez-Niedenfuhr M., Gil J., Peters G.;
RT "Several distinct polycomb complexes regulate and co-localize on the
RT INK4a tumor suppressor locus.";
RL PLoS ONE 4:E6380-E6380(2009).
RN [15]
RP IDENTIFICATION IN A PRC1-LIKE COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=21282530; DOI=10.1074/mcp.M110.002642;
RA Vandamme J., Volkel P., Rosnoblet C., Le Faou P., Angrand P.O.;
RT "Interaction proteomics analysis of polycomb proteins defines distinct
RT PRC1 Complexes in mammalian cells.";
RL Mol. Cell. Proteomics 0:0-0(2011).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 5-101 IN COMPLEX WITH RNF2
RP AND ZINC IONS, FUNCTION, MASS SPECTROMETRY, AND SUBUNIT.
RX PubMed=16714294; DOI=10.1074/jbc.M602461200;
RA Li Z., Cao R., Wang M., Myers M.P., Zhang Y., Xu R.M.;
RT "Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase
RT complex.";
RL J. Biol. Chem. 281:20643-20649(2006).
CC -!- FUNCTION: Component of a Polycomb group (PcG) multiprotein PRC1-
CC like complex, a complex class required to maintain the
CC transcriptionally repressive state of many genes, including Hox
CC genes, throughout development. PcG PRC1 complex acts via chromatin
CC remodeling and modification of histones; it mediates
CC monoubiquitination of histone H2A 'Lys-119', rendering chromatin
CC heritably changed in its expressibility. In the PRC1 complex, it
CC is required to stimulate the E3 ubiquitin-protein ligase activity
CC of RNF2/RING2.
CC -!- SUBUNIT: Component of a PRC1-like complex. Interacts with RING1
CC and RING2 (By similarity). Interacts vwith CBX7 and CBX8.
CC Interacts with SPOP. Part of a complex consisting of BMI1, CUL3
CC and SPOP. Interacts with E4F1.
CC -!- INTERACTION:
CC O00257:CBX4; NbExp=4; IntAct=EBI-2341576, EBI-722425;
CC O00257-3:CBX4; NbExp=2; IntAct=EBI-2341576, EBI-4392727;
CC O95503:CBX6; NbExp=3; IntAct=EBI-2341576, EBI-3951758;
CC O95931:CBX7; NbExp=7; IntAct=EBI-2341576, EBI-3923843;
CC Q9HC52:CBX8; NbExp=13; IntAct=EBI-2341576, EBI-712912;
CC P60484:PTEN; NbExp=3; IntAct=EBI-2341576, EBI-696162;
CC Q06587:RING1; NbExp=11; IntAct=EBI-2341576, EBI-752313;
CC Q99496:RNF2; NbExp=9; IntAct=EBI-2341576, EBI-722416;
CC P0CG48:UBC; NbExp=2; IntAct=EBI-2341576, EBI-3390054;
CC P51784:USP11; NbExp=7; IntAct=EBI-2341576, EBI-306876;
CC Q93009:USP7; NbExp=7; IntAct=EBI-2341576, EBI-302474;
CC Q9H270:VPS11; NbExp=2; IntAct=EBI-2341576, EBI-373380;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm.
CC -!- PTM: Monoubiquitinated (By similarity). May be polyubiquitinated;
CC which does not lead to proteasomal degradation.
CC -!- MISCELLANEOUS: The hPRC-H complex purification reported by
CC PubMed:12167701 probably presents a mixture of different PRC1-like
CC complexes.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/BMI1ID807ch10p12.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L13689; AAA19873.1; -; mRNA.
DR EMBL; AK313235; BAG36046.1; -; mRNA.
DR EMBL; AL158211; CAI15958.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86148.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86150.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86151.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86154.1; -; Genomic_DNA.
DR EMBL; BC011652; AAH11652.1; -; mRNA.
DR EMBL; AH004292; AAB27059.1; -; mRNA.
DR PIR; I54339; I54339.
DR RefSeq; NP_001190991.1; NM_001204062.1.
DR RefSeq; NP_005171.4; NM_005180.8.
DR RefSeq; XP_005252619.1; XM_005252562.1.
DR RefSeq; XP_005252620.1; XM_005252563.1.
DR UniGene; Hs.380403; -.
DR UniGene; Hs.731287; -.
DR PDB; 2H0D; X-ray; 2.50 A; A=5-101.
DR PDB; 3RPG; X-ray; 2.65 A; B=1-109.
DR PDBsum; 2H0D; -.
DR PDBsum; 3RPG; -.
DR ProteinModelPortal; P35226; -.
DR SMR; P35226; 6-103.
DR DIP; DIP-41879N; -.
DR IntAct; P35226; 35.
DR MINT; MINT-158260; -.
DR STRING; 9606.ENSP00000365851; -.
DR PhosphoSite; P35226; -.
DR DMDM; 22258801; -.
DR PaxDb; P35226; -.
DR PRIDE; P35226; -.
DR DNASU; 648; -.
DR Ensembl; ENST00000376663; ENSP00000365851; ENSG00000168283.
DR GeneID; 100532731; -.
DR GeneID; 648; -.
DR KEGG; hsa:100532731; -.
DR KEGG; hsa:648; -.
DR UCSC; uc001irh.3; human.
DR CTD; 100532731; -.
DR CTD; 648; -.
DR GeneCards; GC10P022605; -.
DR HGNC; HGNC:1066; BMI1.
DR HPA; CAB011120; -.
DR HPA; HPA030472; -.
DR MIM; 164831; gene.
DR neXtProt; NX_P35226; -.
DR PharmGKB; PA25376; -.
DR eggNOG; NOG304672; -.
DR HOGENOM; HOG000231945; -.
DR HOVERGEN; HBG052826; -.
DR InParanoid; P35226; -.
DR KO; K11459; -.
DR OMA; RVRPNCK; -.
DR PhylomeDB; P35226; -.
DR Reactome; REACT_120956; Cellular responses to stress.
DR EvolutionaryTrace; P35226; -.
DR GeneWiki; BMI1; -.
DR NextBio; 2628; -.
DR PRO; PR:P35226; -.
DR ArrayExpress; P35226; -.
DR Bgee; P35226; -.
DR CleanEx; HS_BMI1; -.
DR Genevestigator; P35226; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0035102; C:PRC1 complex; IDA:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0016568; P:chromatin modification; IEA:UniProtKB-KW.
DR GO; GO:0030097; P:hemopoiesis; IEP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IMP:UniProtKB.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IMP:BHF-UCL.
DR GO; GO:0051443; P:positive regulation of ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0007379; P:segment specification; TAS:ProtInc.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR018957; Znf_C3HC4_RING-type.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR Pfam; PF00097; zf-C3HC4; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chromatin regulator; Complete proteome; Cytoplasm;
KW Metal-binding; Nucleus; Polymorphism; Proto-oncogene;
KW Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1 326 Polycomb complex protein BMI-1.
FT /FTId=PRO_0000055987.
FT ZN_FING 18 57 RING-type.
FT REGION 164 228 Interaction with E4F1.
FT MOTIF 81 95 Nuclear localization signal (Potential).
FT COMPBIAS 251 326 Pro/Ser-rich.
FT VARIANT 18 18 C -> Y (in dbSNP:rs1042059).
FT /FTId=VAR_052087.
FT CONFLICT 109 109 G -> S (in Ref. 6; AAB27059).
FT CONFLICT 265 265 I -> V (in Ref. 1; AAA19873).
FT STRAND 6 8
FT HELIX 9 12
FT HELIX 13 15
FT TURN 19 21
FT STRAND 22 24
FT STRAND 29 31
FT TURN 32 34
FT HELIX 40 46
FT TURN 54 56
FT HELIX 65 68
FT STRAND 69 71
FT HELIX 73 82
FT HELIX 86 100
SQ SEQUENCE 326 AA; 36949 MW; 030A7D396BADA543 CRC64;
MHRTTRIKIT ELNPHLMCVL CGGYFIDATT IIECLHSFCK TCIVRYLETS KYCPICDVQV
HKTRPLLNIR SDKTLQDIVY KLVPGLFKNE MKRRRDFYAA HPSADAANGS NEDRGEVADE
DKRIITDDEI ISLSIEFFDQ NRLDRKVNKD KEKSKEEVND KRYLRCPAAM TVMHLRKFLR
SKMDIPNTFQ IDVMYEEEPL KDYYTLMDIA YIYTWRRNGP LPLKYRVRPT CKRMKISHQR
DGLTNAGELE SDSGSDKANS PAGGIPSTSS CLPSPSTPVQ SPHPQFPHIS STMNGTSNSP
SGNHQSSFAN RPRKSSVNGS SATSSG
//
MIM
164831
*RECORD*
*FIELD* NO
164831
*FIELD* TI
*164831 LEUKEMIA VIRAL BMI-1 ONCOGENE, MOUSE, HOMOLOG OF; BMI1
*FIELD* TX
CLONING
read more
Transgenic mice bearing oncogenes provide valuable new insights into the
process of malignant transformation. One of the best studied transgenic
mouse models of hematopoietic malignancies is the transgenic mouse
overexpressing the c-myc gene in its lymphoid compartment by virtue of
the immunoglobulin heavy chain enhancer (E-mu). These mice develop
B-cell lymphomas of clonal origin after a variable latency period.
Infection of E-mu/myc transgenic mice with Moloney murine leukemia virus
(MuLV) is an efficient way to identify oncogenes that synergize with the
transgene. In about half of independently induced pre-B-cell lymphomas,
the provirus integrates in or near the Bmi1 gene, resulting in enhanced
transcription of that gene. The murine Bmi1 protein is found in the
nucleus and harbors structural motifs found in nuclear proteins,
including a novel putative zinc finger shared by a diverse set of
proteins involved in gene regulation, DNA recombination, and DNA repair.
The product of the Bmi1 gene showed 70% identity with the Mel18 protein
gene (165040), which was isolated from a mouse melanoma cell line. The
Bmi1 gene is highly conserved in evolution as indicated by zoo blot
hybridization with Bmi1 probes corresponding to the protein-encoding
domain. Alkema et al. (1993) isolated the human BMI1 cDNA. The 3,203-bp
cDNA shows 86% identity to the mouse nucleotide sequence. The open
reading frame encodes a protein of 326 amino acids which shares 98%
identity to the 324-amino acid sequence of the mouse protein.
GENE FUNCTION
While screening for proteins that interact with the BMI1 protein, Satijn
et al. (1997) isolated the RING1 protein (602045). They showed that BMI1
and RING1 bind in vitro and colocalize in the nuclei of 2 types of
sarcoma cells. Satijn et al. (1997) stated that BMI1 and RING1 may be
part of a protein complex.
According to Lessard and Sauvageau (2003) an emerging concept in the
field of cancer biology is that a rare population of 'tumor stem cells'
exists among the heterogeneous group of cells that constitute a tumor.
This concept, best described with human leukemia, indicates that stem
cell function (whether normal or neoplastic) might be defined by a
common set of critical genes. Lessard and Sauvageau (2003) showed that
BMI1 has a key role in regulating the proliferative activity of normal
stem and progenitor cells. Most importantly, they provided evidence that
the proliferative potential of leukemic stem and progenitor cells
lacking BMI1 is compromised because they eventually undergo
proliferation arrest and show signs of differentiation and apoptosis,
leading to transplant failure of the leukemia. Complementation studies
showed that BMI1 completely rescues these proliferative defects. Lessard
and Sauvageau (2003) concluded that BMI1 has an essential role in
regulating the proliferative activity of both normal and leukemic stem
cells.
Itahana et al. (2003) stated that BMI1 represses the INK4A locus which
encodes the tumor suppressors p16(INK4A) and p14(ARF). They found that
BMI1 was downregulated during replicative senescence, but not
quiescence, in a human fibroblast cell line. Furthermore, overexpression
extended the replicative life span of the fibroblasts, and required RB1
(614041) but not p53 (191170). Deletion analysis showed that the RING
finger and helix-turn-helix domains of BMI1 were required for life span
extension and repression of the tumor suppressor p16(INK4). Furthermore,
a RING finger deletion mutant that exhibited dominant negative activity
induced p16(INK4) and premature senescence. Some presenescent cultures
contained growth-arrested cells expressing high levels of p16(INK4) and
were apparently arrested by a p53- and telomere-independent mechanism.
BMI1 selectively extended the life span of these cultures.
Wang et al. (2004) showed that an E3 ubiquitin ligase complex, which
they designated Polycomb repressive complex-1-like (PRC1L), specifically
monoubiquitinates histone-2A (H2A; see 142711) at lys119. They found
that PRC1L is composed of several PcG proteins, including RING1, RNF2
(608985), BMI1, and HPH2 (EDR2; 602979). Reduction of RNF2 expression
resulted in a dramatic decrease in the level of ubiquitinated H2A in
HeLa cells. Wang et al. (2004) proposed that H2A ubiquitination is
linked to Polycomb silencing.
By analyzing proteins that immunoprecipitated with anti-CENPA (117139)
antibodies from HeLa cell nuclear lysates, Obuse et al. (2004) showed
that BMI1 associated with a centromeric complex, which also contained
the major centromeric proteins CENPB (117140), CENPC (117141), CENPH
(605607), CENPI (300065), and MIS12 (609178), and many others. Confocal
microscopy showed that BMI1 transiently colocalized with centromeres
during interphase in HeLa cells.
Guo et al. (2007) found that expression of MEL18 (PCGF2; 600346)
negatively correlated with BMI1 in several human breast cancer cell
lines and in a significant number of breast tumors. Overexpression of
MEL18 in the MCF7 breast cancer cell line downregulated BMI1 and reduced
the transformed phenotype. Furthermore, reduced BMI1 expression in MCF7
cells by MEL18 overexpression or by RNA interference was accompanied by
downregulation of AKT (164730) activity. Overexpression of
constitutively active AKT restored the malignant phenotype in MCF7 cells
with reduced BMI1 expression. Guo et al. (2007) concluded that MEL18
acts as a tumor suppressor in breast cancer cells by repressing BMI1
expression and downregulating AKT activity.
To investigate the role of BMI1 in adult stem cell populations,
Sangiorgi and Capecchi (2008) generated a mouse expressing a
tamoxifen-inducible Cre from the Bmi1 locus. They found that Bmi1 is
expressed in discrete cells located near the bottom of crypts in the
small intestine, predominantly 4 cells above the base of the crypt (+4
position). Over time, these cells proliferate, expand, self-renew, and
give rise to all the differentiated cell lineages of the small intestine
epithelium. The induction of a stable form of beta-catenin (116806) in
these cells was sufficient to rapidly generate adenomas. Moreover,
ablation of Bmi1+ cells using a Rosa26 conditional allele, expressing
diphtheria toxin, led to crypt loss. Sangiorgi and Capecchi (2008)
concluded that their experiments identified Bmi1 as an intestinal stem
cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing
stem cells along the length of the small intestine suggested that
mammals use more than 1 molecularly distinguishable adult stem cell
subpopulation to maintain organ homeostasis.
Using RT-PCR and flow cytometric analysis, Heffner and Fearon (2007)
found that Bmi1 expression increased in mouse Cd8 (see 186910)-positive
T cells in an antigen dose- and time-dependent manner. Expression of
Bmi1 could be reversed by removal of antigen or maintained by
stimulation of Il2r (147730). Suppression of Bmi1 by lentivirally
encoded short hairpin RNA inhibited proliferation of a mouse T-cell line
and primary Cd8-positive T cells. Ectopic expression of Bmi1 enhanced
the expansion of primary Cd8-positive T cells in vitro when stimulated
by Il2 (147680) and Il7 (146660). Increased Bmi1 expression was detected
after stimulation of naive Cd44-low (107269)/Cd8-positive T cells and
memory Cd44-high/Klrg1 (604874)-negative/Cd8-positive T cells, but not
after stimulation of Klrg1-positive/Cd8-positive T cells.
Klrg1-positive/Cd8-positive T cells had elevated levels of p16Ink4a and
p19Arf, products of the Cdkn2a gene (600160) that is transcriptionally
repressed by Bmi1. Heffner and Fearon (2007) concluded that BMI1 is
required for optimal proliferation of CD8-positive T cells and that
T-cell receptor ligation causes its expression in naive and
KLRG1-negative memory cells, but not in senescent, KLRG1-positive T
cells.
Liu et al. (2009) demonstrated that cells derived from Bmi1 -/- mice
have impaired mitochondrial function, a marked increase in the
intracellular levels of reactive oxygen species, and subsequent
engagement of the DNA damage response pathway. Furthermore, many of the
deficiencies normally observed in Bmi1 -/- mice improve after either
pharmacologic treatment with the antioxidant N-acetylcysteine or genetic
disruption of the DNA damage response pathway by Chk2 (CHEK2; 604373)
deletion. Liu et al. (2009) concluded that Bmi1 has an unexpected role
in maintaining mitochondrial function and redox homeostasis, and that
the Polycomb family of proteins can coordinately regulate cellular
metabolism with stem and progenitor cell function.
Two principal epithelial stem cell pools exist in small intestine:
columnar Lgr5 (606667)-expressing cells, which cycle rapidly and are
present predominantly at the crypt base, and Bmi1-expressing cells,
which reside largely above the crypt base. Using a human diphtheria
toxin receptor (DTR) gene knocked into the Lgr5 locus, Tian et al.
(2011) specifically ablated Lgr5-expressing cells in mice. They authors
found that complete loss of the Lgr5-expressing cells did not perturb
homeostasis of the epithelium, indicating that other cell types can
compensate for the elimination of this population. After ablation of
Lgr5-expressing cells, progeny production by Bmi1-expressing cells
increased, indicating that Bmi1-expressing stem cells compensate for the
loss of Lgr5-expressing cells. Indeed, lineage tracing showed that
Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a
hierarchy of stem cells in the intestinal epithelium. Tian et al. (2011)
concluded that their results demonstrated that Lgr5-expressing cells are
dispensable for normal intestinal homeostasis, and that in the absence
of these cells, Bmi1-expressing cells can serve as an alternative stem
cell pool. Tian et al. (2011) suggested that the Bmi1-expressing stem
cells may represent both a reserve stem cell pool in case of injury to
the small intestine epithelium and a source for replenishment of the
Lgr5-expressing cells under nonpathologic conditions.
GENE STRUCTURE
Alkema et al. (1993) determined that the human BMI1 gene consists of at
least 10 exons. The murine Bmi1 gene consists of 10 exons.
MAPPING
Alkema et al. (1993) assigned the human BMI1 gene to chromosome 10p13 by
fluorescence in situ hybridization. The authors stated that the region
10p13 is known to be involved in translocations in various leukemias.
ANIMAL MODEL
The protein encoded by the BMI1 gene has a domain of homology to a
Drosophila protein encoded by a member of the Polycomb-group gene
family, which is required to maintain the repression of homeotic genes
that regulate the identities of Drosophila segments. The fact that mice
lacking the BMI1 gene showed posterior transformations of the axial
skeleton suggested that the gene may play a similar role in vertebrates.
Alkema et al. (1995) found that transgenic mice overexpressing the Bmi1
protein showed the opposite phenotype, namely a dose-dependent anterior
transformation of vertebral identity. The anterior expression boundary
of the Hoxc5 gene was shifted in the posterior direction, indicating
that Bmi1 is involved in the repression of Hox genes. Thus, BMI1 appears
to be a member of a vertebrate Polycomb complex that regulates segmental
identity by repressing HOX genes throughout development.
Molofsky et al. (2003) showed that in the mouse, Bmi1 is required for
the self-renewal of stem cells in the peripheral and central nervous
systems but not for their survival or differentiation. The reduced
self-renewal of Bmi1-deficient neural stem cells led to their postnatal
depletion. In the absence of Bmi1, the cyclin-dependent kinase inhibitor
gene P16(Ink4a) (600160) was upregulated in neural stem cells, reducing
the rate of proliferation. P16(Ink4a) deficiency partially reversed the
self-renewal defect in Bmi1 null neural stem cells. This conserved
requirement for Bmi1 to promote self-renewal and to repress p16(Ink4a)
expression suggested that a common mechanism regulates the self-renewal
and postnatal persistence of diverse types of stem cells. Restricted
neural progenitors from the gut and forebrain proliferated normally in
the absence of Bmi1. Thus, Molofsky et al. (2003) concluded that BMI1
dependence distinguishes stem cell self-renewal from restricted
progenitor proliferation in these tissues.
Kranc et al. (2003) found that Cited2 (602937) null mouse fibroblasts
showed reduced proliferation that was associated with reduced Bmi1 and
Mel18 (600346) expression, and increased Ink4a/Arf expression. Bmi1- and
Mel18-expressing retroviruses enhanced the proliferation of Cited2 null
fibroblasts, indicating that they function downstream of Cited2. Kranc
et al. (2003) concluded that CITED2 controls the expression of INK4A/ARF
and fibroblast proliferation, at least in part, via the polycomb-group
genes BMI1 and MEL18.
Park et al. (2003) found that adult and fetal mouse and adult human
hematopoietic stem cells (HSCs) express the protooncogene Bmi1. The
number of HSCs in fetal liver of Bmi1 -/- mice was normal. In postnatal
Bmi1 -/- mice, the number of HSCs was markedly reduced. Transplanted
fetal liver and bone marrow cells obtained from Bmi1 -/- mice were able
to contribute only transiently to hematopoiesis. There was no detectable
self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi1
null mice. Gene expression analysis revealed that the expression of stem
cell-associated genes, cell survival genes, transcription factors, and
genes modulating proliferation, including p16(Ink4a) and p19(Arf) (see
600160), was altered in bone marrow cells of the Bmi1 null mice.
Expression of p16(Ink4a) and p19(Arf) in normal HSCs resulted in
proliferative arrest and p53 (191170)-dependent cell death,
respectively. Park et al. (2003) concluded that Bmi1 is essential for
the generation of self-renewing adult HSCs.
Leung et al. (2004) demonstrated that BMI1 is strongly expressed in
proliferating cerebellar precursor cells in mice and humans. Using Bmi1
null mice, Leung et al. (2004) demonstrated a crucial role for Bmi1 in
clonal expansion of granule cell precursors both in vivo and in vitro.
Deregulated proliferation of these progenitor cells, by activation of
the Sonic hedgehog (SHH; 600725) pathway, leads to medulloblastoma
development (see 155255). Leung et al. (2004) also demonstrated linked
overexpression of BMI1 and Patched (601309), suggestive of SHH pathway
activation, in a substantial fraction of primary human medulloblastomas.
Together with the rapid induction of Bmi1 expression on addition of Shh
or on overexpression of the Shh target Gli1 (165220) in cerebellar
granule cell cultures, Leung et al. (2004) concluded that their findings
implicate BMI1 overexpression as an alternative or additive mechanism in
the pathogenesis of medulloblastomas, and highlight a role for
BMI1-containing polycomb complexes in proliferation of cerebellar
precursor cells.
Chagraoui et al. (2006) found that knockdown of E4f1 (603022) levels by
RNA interference was sufficient to rescue the clonogenic and
repopulating ability of Bmi1 -/- mouse hematopoietic cells up to 3
months posttransplantation. They concluded that E4F1 is a key modulator
of BMI1 activity in primitive hematopoietic cells.
Dovey et al. (2008) found that loss of Bmi1 decreased the number and
progression of lung tumors at a very early point in an oncogenic Kras
(190070)-initiated mouse model of lung cancer. This correlated with a
defect in the ability of Bmi1-deficient putative bronchioalveolar stem
cells to proliferate in response to the oncogenic stimulus and depended,
in part, on p19(Arf).
*FIELD* RF
1. Alkema, M. J.; van der Lugt, N. M. T.; Bobeldijk, R. C.; Berns,
A.; van Lohuizen, M.: Transformation of axial skeleton due to overexpression
of bmi-1 in transgenic mice. Nature 374: 724-727, 1995.
2. Alkema, M. J.; Wiegant, J.; Raap, A. K.; Berns, A.; van Lohuizen,
M.: Characterization and chromosomal localization of the human proto-oncogene
BMI-1. Hum. Molec. Genet. 2: 1597-1603, 1993.
3. Chagraoui, J.; Niessen, S. L.; Lessard, J.; Girard, S.; Coulombe,
P.; Sauvageau, M.; Meloche, S.; Sauvageau, G.: E4F1: a novel candidate
factor for mediating BMI1 function in primitive hematopoietic cells. Genes
Dev. 20: 2110-2120, 2006.
4. Dovey, J. S.; Zacharek, S. J.; Kim, C. F.; Lees, J. A.: Bmi1 is
critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc.
Nat. Acad. Sci. 105: 11857-11862, 2008.
5. Guo, W.-J.; Zeng, M.-S.; Yadav, A.; Song, L.-B.; Guo, B.-H.; Band,
V.; Dimri, G. P.: Mel-18 acts as a tumor suppressor by repressing
Bmi-1 expression and down-regulating Akt activity in breast cancer
cells. Cancer Res. 67: 5083-5089, 2007.
6. Heffner, M.; Fearon, D. T.: Loss of T cell receptor-induced Bmi-1
in the KLRG1+ senescent CD8+ T lymphocyte. Proc. Nat. Acad. Sci. 104:
13414-13419, 2007.
7. Itahana, K.; Zou, Y.; Itahana, Y.; Martinez, J.-L.; Beausejour,
C.; Jacobs, J. J. L.; van Lohuizen, M.; Band, V.; Campisi, J.; Dimri,
G. P.: Control of the replicative life span of human fibroblasts
by p16 and the polycomb protein Bmi-1. Molec. Cell. Biol. 23: 389-401,
2003.
8. Kranc, K. R.; Bamforth, S. D.; Braganca, J.; Norbury, C.; van Lohuizen,
M.; Bhattacharya, S.: Transcriptional coactivator Cited2 induces
Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF. Molec.
Cell. Biol. 23: 7658-7666, 2003.
9. Lessard, J.; Sauvageau, G.: Bmi-1 determines the proliferative
capacity of normal and leukaemic stem cells. Nature 423: 255-260,
2003.
10. Leung, C.; Lingbeek, M.; Shakhova, O.; Liu, J.; Tanger, E.; Saremaslani,
P.; van Lohuizen, M.; Marino, S.: Bmi1 is essential for cerebellar
development and is overexpressed in human medulloblastomas. Nature 428:
337-341, 2004.
11. Liu, J.; Cao, J.; Chen, J.; Song, S.; Lee, I. H.; Quijano, C.;
Liu, H.; Keyvanfar, K.; Chen, H.; Cao, L.-Y.; Ahn, B.-H.; Kumar, N.
G.; Rovira, I. I.; Xu, X.-L.; van Lohuizen, M.; Motoyama, N.; Deng,
C.-X.; Finkel, T.: Bmi1 regulates mitochondrial function and the
DNA damage response pathway. Nature 459: 387-392, 2009.
12. Molofsky, A. V.; Pardal, R.; Iwashita, T.; Park, I.-K.; Clarke,
M. F.; Morrison, S. J.: Bmi-1 dependence distinguishes neural stem
cell self-renewal from progenitor proliferation. Nature 425: 962-967,
2003.
13. Obuse, C.; Yang, H.; Nozaki, N.; Goto, S.; Okazaki, T.; Yoda,
K.: Proteomics analysis of the centromere complex from HeLa interphase
cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of
the CEN-complex, while BMI-1 is transiently co-localized with the
centromeric region in interphase. Genes Cells 9: 105-120, 2004.
14. Park, I.; Qian, D.; Kiel, M.; Becker, M. W.; Pihalja, M.; Weissman,
I. L.; Morrison, S. J.; Clarke, M. F.: Bmi-1 is required for maintenance
of adult self-renewing haematopoietic stem cells. Nature 423: 302-305,
2003.
15. Sangiorgi, E.; Capecchi, M. R.: Bmi1 is expressed in vivo in
intestinal stem cells. Nature Genet. 40: 915-920, 2008.
16. Satijn, D. P. E.; Gunster, M. J.; van der Vlag, J.; Hamer, K.
M.; Schul, W.; Alkema, M. J.; Saurin, A. J.; Freemont, P. S.; van
Driel, R.; Otte, A. P.: RING1 is associated with the polycomb group
protein complex and acts as a transcriptional repressor. Molec. Cell.
Biol. 17: 4105-4113, 1997.
17. Tian, H.; Biehs, B.; Warming, S.; Leong, K. G.; Rangell, L.; Klein,
O. D.; de Sauvage, F. J.: A reserve stem cell population in small
intestine renders Lgr5-positive cells dispensable. Nature 478: 255-259,
2011. Note: Erratum: Nature 482: 120 only, 2012.
18. Wang, H.; Wang, L.; Erdjument-Bromage, H.; Vidal, M.; Tempst,
P.; Jones, R. S.; Zhang, Y.: Role of histone H2A ubiquitination in
Polycomb silencing. Nature 431: 873-878, 2004.
*FIELD* CN
Ada Hamosh - updated: 11/22/2011
Patricia A. Hartz - updated: 8/31/2009
Ada Hamosh - updated: 8/17/2009
Paul J. Converse - updated: 10/24/2008
Ada Hamosh - updated: 8/6/2008
Patricia A. Hartz - updated: 3/4/2008
Patricia A. Hartz - updated: 8/10/2007
Patricia A. Hartz - updated: 10/3/2006
Paul J. Converse - updated: 10/21/2004
Ada Hamosh - updated: 4/7/2004
Patricia A. Hartz - updated: 2/18/2004
Ada Hamosh - updated: 10/29/2003
Ada Hamosh - updated: 5/6/2003
Jennifer P. Macke - updated: 10/13/1997
*FIELD* CD
Victor A. McKusick: 11/1/1993
*FIELD* ED
alopez: 04/25/2012
alopez: 2/27/2012
alopez: 11/28/2011
terry: 11/22/2011
carol: 6/17/2011
mgross: 9/4/2009
terry: 8/31/2009
alopez: 8/18/2009
terry: 8/17/2009
mgross: 10/24/2008
terry: 10/8/2008
alopez: 9/9/2008
terry: 8/6/2008
mgross: 3/4/2008
wwang: 10/4/2007
terry: 8/10/2007
mgross: 10/4/2006
terry: 10/3/2006
terry: 10/12/2005
mgross: 10/21/2004
alopez: 4/13/2004
terry: 4/7/2004
cwells: 3/1/2004
terry: 2/18/2004
alopez: 10/31/2003
alopez: 10/30/2003
terry: 10/29/2003
alopez: 5/16/2003
alopez: 5/6/2003
terry: 5/6/2003
alopez: 10/27/1997
alopez: 10/13/1997
randy: 8/31/1996
mark: 5/5/1995
carol: 11/1/1993
*RECORD*
*FIELD* NO
164831
*FIELD* TI
*164831 LEUKEMIA VIRAL BMI-1 ONCOGENE, MOUSE, HOMOLOG OF; BMI1
*FIELD* TX
CLONING
read more
Transgenic mice bearing oncogenes provide valuable new insights into the
process of malignant transformation. One of the best studied transgenic
mouse models of hematopoietic malignancies is the transgenic mouse
overexpressing the c-myc gene in its lymphoid compartment by virtue of
the immunoglobulin heavy chain enhancer (E-mu). These mice develop
B-cell lymphomas of clonal origin after a variable latency period.
Infection of E-mu/myc transgenic mice with Moloney murine leukemia virus
(MuLV) is an efficient way to identify oncogenes that synergize with the
transgene. In about half of independently induced pre-B-cell lymphomas,
the provirus integrates in or near the Bmi1 gene, resulting in enhanced
transcription of that gene. The murine Bmi1 protein is found in the
nucleus and harbors structural motifs found in nuclear proteins,
including a novel putative zinc finger shared by a diverse set of
proteins involved in gene regulation, DNA recombination, and DNA repair.
The product of the Bmi1 gene showed 70% identity with the Mel18 protein
gene (165040), which was isolated from a mouse melanoma cell line. The
Bmi1 gene is highly conserved in evolution as indicated by zoo blot
hybridization with Bmi1 probes corresponding to the protein-encoding
domain. Alkema et al. (1993) isolated the human BMI1 cDNA. The 3,203-bp
cDNA shows 86% identity to the mouse nucleotide sequence. The open
reading frame encodes a protein of 326 amino acids which shares 98%
identity to the 324-amino acid sequence of the mouse protein.
GENE FUNCTION
While screening for proteins that interact with the BMI1 protein, Satijn
et al. (1997) isolated the RING1 protein (602045). They showed that BMI1
and RING1 bind in vitro and colocalize in the nuclei of 2 types of
sarcoma cells. Satijn et al. (1997) stated that BMI1 and RING1 may be
part of a protein complex.
According to Lessard and Sauvageau (2003) an emerging concept in the
field of cancer biology is that a rare population of 'tumor stem cells'
exists among the heterogeneous group of cells that constitute a tumor.
This concept, best described with human leukemia, indicates that stem
cell function (whether normal or neoplastic) might be defined by a
common set of critical genes. Lessard and Sauvageau (2003) showed that
BMI1 has a key role in regulating the proliferative activity of normal
stem and progenitor cells. Most importantly, they provided evidence that
the proliferative potential of leukemic stem and progenitor cells
lacking BMI1 is compromised because they eventually undergo
proliferation arrest and show signs of differentiation and apoptosis,
leading to transplant failure of the leukemia. Complementation studies
showed that BMI1 completely rescues these proliferative defects. Lessard
and Sauvageau (2003) concluded that BMI1 has an essential role in
regulating the proliferative activity of both normal and leukemic stem
cells.
Itahana et al. (2003) stated that BMI1 represses the INK4A locus which
encodes the tumor suppressors p16(INK4A) and p14(ARF). They found that
BMI1 was downregulated during replicative senescence, but not
quiescence, in a human fibroblast cell line. Furthermore, overexpression
extended the replicative life span of the fibroblasts, and required RB1
(614041) but not p53 (191170). Deletion analysis showed that the RING
finger and helix-turn-helix domains of BMI1 were required for life span
extension and repression of the tumor suppressor p16(INK4). Furthermore,
a RING finger deletion mutant that exhibited dominant negative activity
induced p16(INK4) and premature senescence. Some presenescent cultures
contained growth-arrested cells expressing high levels of p16(INK4) and
were apparently arrested by a p53- and telomere-independent mechanism.
BMI1 selectively extended the life span of these cultures.
Wang et al. (2004) showed that an E3 ubiquitin ligase complex, which
they designated Polycomb repressive complex-1-like (PRC1L), specifically
monoubiquitinates histone-2A (H2A; see 142711) at lys119. They found
that PRC1L is composed of several PcG proteins, including RING1, RNF2
(608985), BMI1, and HPH2 (EDR2; 602979). Reduction of RNF2 expression
resulted in a dramatic decrease in the level of ubiquitinated H2A in
HeLa cells. Wang et al. (2004) proposed that H2A ubiquitination is
linked to Polycomb silencing.
By analyzing proteins that immunoprecipitated with anti-CENPA (117139)
antibodies from HeLa cell nuclear lysates, Obuse et al. (2004) showed
that BMI1 associated with a centromeric complex, which also contained
the major centromeric proteins CENPB (117140), CENPC (117141), CENPH
(605607), CENPI (300065), and MIS12 (609178), and many others. Confocal
microscopy showed that BMI1 transiently colocalized with centromeres
during interphase in HeLa cells.
Guo et al. (2007) found that expression of MEL18 (PCGF2; 600346)
negatively correlated with BMI1 in several human breast cancer cell
lines and in a significant number of breast tumors. Overexpression of
MEL18 in the MCF7 breast cancer cell line downregulated BMI1 and reduced
the transformed phenotype. Furthermore, reduced BMI1 expression in MCF7
cells by MEL18 overexpression or by RNA interference was accompanied by
downregulation of AKT (164730) activity. Overexpression of
constitutively active AKT restored the malignant phenotype in MCF7 cells
with reduced BMI1 expression. Guo et al. (2007) concluded that MEL18
acts as a tumor suppressor in breast cancer cells by repressing BMI1
expression and downregulating AKT activity.
To investigate the role of BMI1 in adult stem cell populations,
Sangiorgi and Capecchi (2008) generated a mouse expressing a
tamoxifen-inducible Cre from the Bmi1 locus. They found that Bmi1 is
expressed in discrete cells located near the bottom of crypts in the
small intestine, predominantly 4 cells above the base of the crypt (+4
position). Over time, these cells proliferate, expand, self-renew, and
give rise to all the differentiated cell lineages of the small intestine
epithelium. The induction of a stable form of beta-catenin (116806) in
these cells was sufficient to rapidly generate adenomas. Moreover,
ablation of Bmi1+ cells using a Rosa26 conditional allele, expressing
diphtheria toxin, led to crypt loss. Sangiorgi and Capecchi (2008)
concluded that their experiments identified Bmi1 as an intestinal stem
cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing
stem cells along the length of the small intestine suggested that
mammals use more than 1 molecularly distinguishable adult stem cell
subpopulation to maintain organ homeostasis.
Using RT-PCR and flow cytometric analysis, Heffner and Fearon (2007)
found that Bmi1 expression increased in mouse Cd8 (see 186910)-positive
T cells in an antigen dose- and time-dependent manner. Expression of
Bmi1 could be reversed by removal of antigen or maintained by
stimulation of Il2r (147730). Suppression of Bmi1 by lentivirally
encoded short hairpin RNA inhibited proliferation of a mouse T-cell line
and primary Cd8-positive T cells. Ectopic expression of Bmi1 enhanced
the expansion of primary Cd8-positive T cells in vitro when stimulated
by Il2 (147680) and Il7 (146660). Increased Bmi1 expression was detected
after stimulation of naive Cd44-low (107269)/Cd8-positive T cells and
memory Cd44-high/Klrg1 (604874)-negative/Cd8-positive T cells, but not
after stimulation of Klrg1-positive/Cd8-positive T cells.
Klrg1-positive/Cd8-positive T cells had elevated levels of p16Ink4a and
p19Arf, products of the Cdkn2a gene (600160) that is transcriptionally
repressed by Bmi1. Heffner and Fearon (2007) concluded that BMI1 is
required for optimal proliferation of CD8-positive T cells and that
T-cell receptor ligation causes its expression in naive and
KLRG1-negative memory cells, but not in senescent, KLRG1-positive T
cells.
Liu et al. (2009) demonstrated that cells derived from Bmi1 -/- mice
have impaired mitochondrial function, a marked increase in the
intracellular levels of reactive oxygen species, and subsequent
engagement of the DNA damage response pathway. Furthermore, many of the
deficiencies normally observed in Bmi1 -/- mice improve after either
pharmacologic treatment with the antioxidant N-acetylcysteine or genetic
disruption of the DNA damage response pathway by Chk2 (CHEK2; 604373)
deletion. Liu et al. (2009) concluded that Bmi1 has an unexpected role
in maintaining mitochondrial function and redox homeostasis, and that
the Polycomb family of proteins can coordinately regulate cellular
metabolism with stem and progenitor cell function.
Two principal epithelial stem cell pools exist in small intestine:
columnar Lgr5 (606667)-expressing cells, which cycle rapidly and are
present predominantly at the crypt base, and Bmi1-expressing cells,
which reside largely above the crypt base. Using a human diphtheria
toxin receptor (DTR) gene knocked into the Lgr5 locus, Tian et al.
(2011) specifically ablated Lgr5-expressing cells in mice. They authors
found that complete loss of the Lgr5-expressing cells did not perturb
homeostasis of the epithelium, indicating that other cell types can
compensate for the elimination of this population. After ablation of
Lgr5-expressing cells, progeny production by Bmi1-expressing cells
increased, indicating that Bmi1-expressing stem cells compensate for the
loss of Lgr5-expressing cells. Indeed, lineage tracing showed that
Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a
hierarchy of stem cells in the intestinal epithelium. Tian et al. (2011)
concluded that their results demonstrated that Lgr5-expressing cells are
dispensable for normal intestinal homeostasis, and that in the absence
of these cells, Bmi1-expressing cells can serve as an alternative stem
cell pool. Tian et al. (2011) suggested that the Bmi1-expressing stem
cells may represent both a reserve stem cell pool in case of injury to
the small intestine epithelium and a source for replenishment of the
Lgr5-expressing cells under nonpathologic conditions.
GENE STRUCTURE
Alkema et al. (1993) determined that the human BMI1 gene consists of at
least 10 exons. The murine Bmi1 gene consists of 10 exons.
MAPPING
Alkema et al. (1993) assigned the human BMI1 gene to chromosome 10p13 by
fluorescence in situ hybridization. The authors stated that the region
10p13 is known to be involved in translocations in various leukemias.
ANIMAL MODEL
The protein encoded by the BMI1 gene has a domain of homology to a
Drosophila protein encoded by a member of the Polycomb-group gene
family, which is required to maintain the repression of homeotic genes
that regulate the identities of Drosophila segments. The fact that mice
lacking the BMI1 gene showed posterior transformations of the axial
skeleton suggested that the gene may play a similar role in vertebrates.
Alkema et al. (1995) found that transgenic mice overexpressing the Bmi1
protein showed the opposite phenotype, namely a dose-dependent anterior
transformation of vertebral identity. The anterior expression boundary
of the Hoxc5 gene was shifted in the posterior direction, indicating
that Bmi1 is involved in the repression of Hox genes. Thus, BMI1 appears
to be a member of a vertebrate Polycomb complex that regulates segmental
identity by repressing HOX genes throughout development.
Molofsky et al. (2003) showed that in the mouse, Bmi1 is required for
the self-renewal of stem cells in the peripheral and central nervous
systems but not for their survival or differentiation. The reduced
self-renewal of Bmi1-deficient neural stem cells led to their postnatal
depletion. In the absence of Bmi1, the cyclin-dependent kinase inhibitor
gene P16(Ink4a) (600160) was upregulated in neural stem cells, reducing
the rate of proliferation. P16(Ink4a) deficiency partially reversed the
self-renewal defect in Bmi1 null neural stem cells. This conserved
requirement for Bmi1 to promote self-renewal and to repress p16(Ink4a)
expression suggested that a common mechanism regulates the self-renewal
and postnatal persistence of diverse types of stem cells. Restricted
neural progenitors from the gut and forebrain proliferated normally in
the absence of Bmi1. Thus, Molofsky et al. (2003) concluded that BMI1
dependence distinguishes stem cell self-renewal from restricted
progenitor proliferation in these tissues.
Kranc et al. (2003) found that Cited2 (602937) null mouse fibroblasts
showed reduced proliferation that was associated with reduced Bmi1 and
Mel18 (600346) expression, and increased Ink4a/Arf expression. Bmi1- and
Mel18-expressing retroviruses enhanced the proliferation of Cited2 null
fibroblasts, indicating that they function downstream of Cited2. Kranc
et al. (2003) concluded that CITED2 controls the expression of INK4A/ARF
and fibroblast proliferation, at least in part, via the polycomb-group
genes BMI1 and MEL18.
Park et al. (2003) found that adult and fetal mouse and adult human
hematopoietic stem cells (HSCs) express the protooncogene Bmi1. The
number of HSCs in fetal liver of Bmi1 -/- mice was normal. In postnatal
Bmi1 -/- mice, the number of HSCs was markedly reduced. Transplanted
fetal liver and bone marrow cells obtained from Bmi1 -/- mice were able
to contribute only transiently to hematopoiesis. There was no detectable
self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi1
null mice. Gene expression analysis revealed that the expression of stem
cell-associated genes, cell survival genes, transcription factors, and
genes modulating proliferation, including p16(Ink4a) and p19(Arf) (see
600160), was altered in bone marrow cells of the Bmi1 null mice.
Expression of p16(Ink4a) and p19(Arf) in normal HSCs resulted in
proliferative arrest and p53 (191170)-dependent cell death,
respectively. Park et al. (2003) concluded that Bmi1 is essential for
the generation of self-renewing adult HSCs.
Leung et al. (2004) demonstrated that BMI1 is strongly expressed in
proliferating cerebellar precursor cells in mice and humans. Using Bmi1
null mice, Leung et al. (2004) demonstrated a crucial role for Bmi1 in
clonal expansion of granule cell precursors both in vivo and in vitro.
Deregulated proliferation of these progenitor cells, by activation of
the Sonic hedgehog (SHH; 600725) pathway, leads to medulloblastoma
development (see 155255). Leung et al. (2004) also demonstrated linked
overexpression of BMI1 and Patched (601309), suggestive of SHH pathway
activation, in a substantial fraction of primary human medulloblastomas.
Together with the rapid induction of Bmi1 expression on addition of Shh
or on overexpression of the Shh target Gli1 (165220) in cerebellar
granule cell cultures, Leung et al. (2004) concluded that their findings
implicate BMI1 overexpression as an alternative or additive mechanism in
the pathogenesis of medulloblastomas, and highlight a role for
BMI1-containing polycomb complexes in proliferation of cerebellar
precursor cells.
Chagraoui et al. (2006) found that knockdown of E4f1 (603022) levels by
RNA interference was sufficient to rescue the clonogenic and
repopulating ability of Bmi1 -/- mouse hematopoietic cells up to 3
months posttransplantation. They concluded that E4F1 is a key modulator
of BMI1 activity in primitive hematopoietic cells.
Dovey et al. (2008) found that loss of Bmi1 decreased the number and
progression of lung tumors at a very early point in an oncogenic Kras
(190070)-initiated mouse model of lung cancer. This correlated with a
defect in the ability of Bmi1-deficient putative bronchioalveolar stem
cells to proliferate in response to the oncogenic stimulus and depended,
in part, on p19(Arf).
*FIELD* RF
1. Alkema, M. J.; van der Lugt, N. M. T.; Bobeldijk, R. C.; Berns,
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factor for mediating BMI1 function in primitive hematopoietic cells. Genes
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5. Guo, W.-J.; Zeng, M.-S.; Yadav, A.; Song, L.-B.; Guo, B.-H.; Band,
V.; Dimri, G. P.: Mel-18 acts as a tumor suppressor by repressing
Bmi-1 expression and down-regulating Akt activity in breast cancer
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6. Heffner, M.; Fearon, D. T.: Loss of T cell receptor-induced Bmi-1
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8. Kranc, K. R.; Bamforth, S. D.; Braganca, J.; Norbury, C.; van Lohuizen,
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11. Liu, J.; Cao, J.; Chen, J.; Song, S.; Lee, I. H.; Quijano, C.;
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K.: Proteomics analysis of the centromere complex from HeLa interphase
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the CEN-complex, while BMI-1 is transiently co-localized with the
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15. Sangiorgi, E.; Capecchi, M. R.: Bmi1 is expressed in vivo in
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*FIELD* CN
Ada Hamosh - updated: 11/22/2011
Patricia A. Hartz - updated: 8/31/2009
Ada Hamosh - updated: 8/17/2009
Paul J. Converse - updated: 10/24/2008
Ada Hamosh - updated: 8/6/2008
Patricia A. Hartz - updated: 3/4/2008
Patricia A. Hartz - updated: 8/10/2007
Patricia A. Hartz - updated: 10/3/2006
Paul J. Converse - updated: 10/21/2004
Ada Hamosh - updated: 4/7/2004
Patricia A. Hartz - updated: 2/18/2004
Ada Hamosh - updated: 10/29/2003
Ada Hamosh - updated: 5/6/2003
Jennifer P. Macke - updated: 10/13/1997
*FIELD* CD
Victor A. McKusick: 11/1/1993
*FIELD* ED
alopez: 04/25/2012
alopez: 2/27/2012
alopez: 11/28/2011
terry: 11/22/2011
carol: 6/17/2011
mgross: 9/4/2009
terry: 8/31/2009
alopez: 8/18/2009
terry: 8/17/2009
mgross: 10/24/2008
terry: 10/8/2008
alopez: 9/9/2008
terry: 8/6/2008
mgross: 3/4/2008
wwang: 10/4/2007
terry: 8/10/2007
mgross: 10/4/2006
terry: 10/3/2006
terry: 10/12/2005
mgross: 10/21/2004
alopez: 4/13/2004
terry: 4/7/2004
cwells: 3/1/2004
terry: 2/18/2004
alopez: 10/31/2003
alopez: 10/30/2003
terry: 10/29/2003
alopez: 5/16/2003
alopez: 5/6/2003
terry: 5/6/2003
alopez: 10/27/1997
alopez: 10/13/1997
randy: 8/31/1996
mark: 5/5/1995
carol: 11/1/1993