BMI1

From Wikipedia, the free encyclopedia

BMI1 polycomb ring finger oncogene

PDB rendering based on 2ckl.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
2H0D, 3RPG

Identifiers

Symbols

BMI1; FLVI2/BMI1; PCGF4; RNF51

External IDs

OMIM: 164831 MGI: 88174 HomoloGene: 121964 GeneCards: BMI1 Gene

Gene Ontology
Molecular function	• chromatin binding • ubiquitin-protein ligase activity • protein binding • zinc ion binding • sequence-specific DNA binding • RING-like zinc finger domain binding
Cellular component	• ubiquitin ligase complex • nucleus • nucleolus • cytoplasm • nuclear body • PcG protein complex • PRC1 complex
Biological process	• negative regulation of transcription from RNA polymerase II promoter • in utero embryonic development • transcription, DNA-dependent • humoral immune response • segment specification • brain development • regulation of gene expression • histone acetylation • histone ubiquitination • rostrocaudal neural tube patterning • hemopoiesis • positive regulation of B cell proliferation • positive regulation of immature T cell proliferation in thymus • negative regulation of apoptotic process • somatic stem cell division • positive regulation of fibroblast proliferation • embryonic skeletal system morphogenesis • positive regulation of ubiquitin-protein ligase activity
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 10:
22.61 – 22.62 Mb

Chr 2:
18.6 – 18.61 Mb

PubMed search

Polycomb complex protein BMI-1 also known as polycomb group RING finger protein 4 (PCGF4) or RING finger protein 51 (RNF51) is a protein that in humans is encoded by the BMI1 gene (B cell-specific Moloney murine leukemia virus integration site 1).^[1]^[2] BMI1 is a polycomb ring finger oncogene.

Function

BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) has been reported as an oncogene by regulating p16 and p19, which are cell cycle inhibitor genes. Bmi1 knockout in mice results in defects in hematopoiesis, skeletal patterning, neurological functions, and development of the cerebellum. Recently it has been reported BMI1 is rapidly recruited to sites of DNA damage and it sustains for over than 8h. Loss of BMI1 leads to radiation sensitive and impaired repair of DNA double-strand breaks by homologous recombination 10.

Bmi1 is necessary for efficient self-renewing cell divisions of adult hematopoietic stem cells as well as adult peripheral and central nervous system neural stem cells.^[3]^[4] However, it is less important for the generation of differentiated progeny. Given that phenotypic changes in Bmi1 knockout mice are numerous and that Bmi1 has very broad tissue distribution, it is possible that it regulates the self-renewal of other types of somatic stem cells.^[5]

Bmi1 is also thought to inhibit ageing in neurons through the suppression of p53.^[6]

Structure

Bmi1 has a RING finger at the N-terminus and a central helix-turn-helix domain.^[7]

Clinical significance

Overexpression of Bmi1 seems to play an important role in several types of cancer, such as bladder, skin, prostate, breast, ovarian, colorectal as well as hematological malignancies. Its amplification and overexpression is especially pronounced in mantle cell lymphomas.^[8] Inhibiting BMI1 has been shown to inhibit the proliferation of glioblastoma multiforme, chemoresistant ovarian cancer, prostatic, pancreatic and skin cancers.^[2] Colorectal cancer stem cell self-renewal was reduced by BMI1 inhibition.^[9]

Interactions

BMI1 has been shown to interact with:

References

↑ Alkema MJ, Wiegant J, Raap AK, Berns A, van Lohuizen M (October 1993). "Characterization and chromosomal localization of the human proto-oncogene BMI-1". Hum. Mol. Genet. 2 (10): 1597–603. doi:10.1093/hmg/2.10.1597. PMID 8268912.
↑ 2.0 2.1 Siddique HR, Saleem M (March 2012). "Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences". Stem Cells 30 (3): 372–8. doi:10.1002/stem.1035. PMID 22252887.
↑ Lessard J, Sauvageau G (May 2003). "Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells". Nature 423 (6937): 255–60. doi:10.1038/nature01572. PMID 12714970.
↑ Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (June 2005). "Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways". Genes Dev. 19 (12): 1432–7. doi:10.1101/gad.1299505. PMC 1151659. PMID 15964994.
↑ Park IK, Morrison SJ, Clarke MF (January 2004). "Bmi1, stem cells, and senescence regulation". J. Clin. Invest. 113 (2): 175–9. doi:10.1172/JCI20800. PMC 311443. PMID 14722607.
↑ Chatoo W, Abdouh M, David J, Champagne MP, Ferreira J, Rodier F, Bernier G (January 2009). "The polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity". J. Neurosci. 29 (2): 529–42. doi:10.1523/JNEUROSCI.5303-08.2009. PMC 2744209. PMID 19144853.
↑ Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J, Dimri GP (January 2003). "Control of the Replicative Life Span of Human Fibroblasts by p16 and the Polycomb Protein Bmi-1". Mol. Cell. Biol. 23 (1): 389–401. doi:10.1128/MCB.23.1.389-401.2003. PMC 140680. PMID 12482990.
↑ Shakhova O, Leung C, Marino S (August 2005). "Bmi1 in development and tumorigenesis of the central nervous system". J. Mol. Med. 83 (8): 596–600. doi:10.1007/s00109-005-0682-0. PMID 15976916.
↑ Kreso A, van Galen P, Pedley M, Lima-Fernandes E, Frelin C, Davis T, Cao L, Baiazitov R, Du W, Sydorenko N, Moon Y-C, Gibson L, Wang Y, Leung C, Iscove NN, Arrowsmith CH, Szentgyorogyi E, Gallinger S, Dick JE, O'Brien CA (January 2014). "Self-renewal as a therapeutic target in human colorectal cancer". Nat. Med. 20: 29–36. doi:10.1038/nm.3418. PMID 24292392.
↑ 10.0 10.1 Gunster MJ, Satijn DP, Hamer KM, den Blaauwen JL, de Bruijn D, Alkema MJ, van Lohuizen M, van Driel R, Otte AP (April 1997). "Identification and characterization of interactions between the vertebrate polycomb-group protein BMI1 and human homologs of polyhomeotic". Mol. Cell. Biol. 17 (4): 2326–35. PMC 232081. PMID 9121482.
↑ 11.0 11.1 Satijn DP, Gunster MJ, van der Vlag J, Hamer KM, Schul W, Alkema MJ, Saurin AJ, Freemont PS, van Driel R, Otte AP (July 1997). "RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor". Mol. Cell. Biol. 17 (7): 4105–13. PMC 232264. PMID 9199346.
↑ Satijn DP, Otte AP (January 1999). "RING1 interacts with multiple Polycomb-group proteins and displays tumorigenic activity". Mol. Cell. Biol. 19 (1): 57–68. PMC 83865. PMID 9858531.
↑ Barna M, Merghoub T, Costoya JA, Ruggero D, Branford M, Bergia A, Samori B, Pandolfi PP (October 2002). "Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling". Dev. Cell 3 (4): 499–510. doi:10.1016/S1534-5807(02)00289-7. PMID 12408802.

Ginjala V, Nacerddine K, Kulkarni A, Oza J, Hill SJ, Yao M, Citterio E, van Lohuizen M, Ganesan S (May 2011). "BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair". Mol. Cell. Biol. 31 (10): 1972–82. doi:10.1128/MCB.00981-10. PMC 3133356. PMID 21383063.
Alkema MJ, van der Lugt NM, Bobeldijk RC, et al. (1995). "Transformation of axial skeleton due to overexpression of bmi-1 in transgenic mice". Nature 374 (6524): 724–7. doi:10.1038/374724a0. PMID 7715727.
Alkema MJ, Wiegant J, Raap AK, et al. (1994). "Characterization and chromosomal localization of the human proto-oncogene BMI-1". Hum. Mol. Genet. 2 (10): 1597–603. doi:10.1093/hmg/2.10.1597. PMID 8268912.
Levy LS, Lobelle-Rich PA, Overbaugh J (1993). "flvi-2, a target of retroviral insertional mutagenesis in feline thymic lymphosarcomas, encodes bmi-1". Oncogene 8 (7): 1833–8. PMID 8390036.
Alkema MJ, Bronk M, Verhoeven E, et al. (1997). "Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex". Genes Dev. 11 (2): 226–40. doi:10.1101/gad.11.2.226. PMID 9009205.
Gunster MJ, Satijn DP, Hamer KM, et al. (1997). "Identification and characterization of interactions between the vertebrate polycomb-group protein BMI1 and human homologs of polyhomeotic". Mol. Cell. Biol. 17 (4): 2326–35. PMC 232081. PMID 9121482.
Satijn DP, Gunster MJ, van der Vlag J, et al. (1997). "RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor". Mol. Cell. Biol. 17 (7): 4105–13. PMC 232264. PMID 9199346.
Alkema MJ, Jacobs J, Voncken JW, et al. (1997). "MPc2, a new murine homolog of the Drosophila polycomb protein is a member of the mouse polycomb transcriptional repressor complex". J. Mol. Biol. 273 (5): 993–1003. doi:10.1006/jmbi.1997.1372. PMID 9367786.
Satijn DP, Otte AP (1999). "RING1 Interacts with Multiple Polycomb-Group Proteins and Displays Tumorigenic Activity". Mol. Cell. Biol. 19 (1): 57–68. PMC 83865. PMID 9858531.
Voncken JW, Schweizer D, Aagaard L, et al. (2000). "Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status". J. Cell. Sci. 112 (24): 4627–39. PMID 10574711.
Bárdos JI, Saurin AJ, Tissot C, et al. (2000). "HPC3 is a new human polycomb orthologue that interacts and associates with RING1 and Bmi1 and has transcriptional repression properties". J. Biol. Chem. 275 (37): 28785–92. doi:10.1074/jbc.M001835200. PMID 10825164.
Trimarchi JM, Fairchild B, Wen J, Lees JA (2001). "The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1519–24. doi:10.1073/pnas.041597698. PMC 29289. PMID 11171983.
Levine SS, Weiss A, Erdjument-Bromage H, et al. (2002). "The Core of the Polycomb Repressive Complex Is Compositionally and Functionally Conserved in Flies and Humans". Mol. Cell. Biol. 22 (17): 6070–8. doi:10.1128/MCB.22.17.6070-6078.2002. PMC 134016. PMID 12167701.
Suzuki M, Mizutani-Koseki Y, Fujimura Y, et al. (2002). "Involvement of the Polycomb-group gene Ring1B in the specification of the anterior-posterior axis in mice". Development 129 (18): 4171–83. PMID 12183370.
Dimri GP, Martinez JL, Jacobs JJ, et al. (2002). "The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells". Cancer Res. 62 (16): 4736–45. PMID 12183433.
Barna M, Merghoub T, Costoya JA, et al. (2002). "Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling". Dev. Cell 3 (4): 499–510. doi:10.1016/S1534-5807(02)00289-7. PMID 12408802.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Cmarko D, Verschure PJ, Otte AP, et al. (2003). "Polycomb group gene silencing proteins are concentrated in the perichromatin compartment of the mammalian nucleus". J. Cell. Sci. 116 (Pt 2): 335–43. doi:10.1242/jcs.00225. PMID 12482919.
Itahana K, Zou Y, Itahana Y, et al. (2003). "Control of the Replicative Life Span of Human Fibroblasts by p16 and the Polycomb Protein Bmi-1". Mol. Cell. Biol. 23 (1): 389–401. doi:10.1128/MCB.23.1.389-401.2003. PMC 140680. PMID 12482990.
Park IK, Qian D, Kiel M, et al. (2003). "Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells". Nature 423 (6937): 302–5. doi:10.1038/nature01587. PMID 12714971.
Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ (2003). "MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein". Proc. Natl. Acad. Sci. U.S.A. 100 (14): 8342–7. doi:10.1073/pnas.1436338100. PMC 166231. PMID 12829790.

PDB gallery

2ckl: RING1B-BMI1 E3 CATALYTIC DOMAIN STRUCTURE

2h0d: Structure of a Bmi-1-Ring1B Polycomb group ubiquitin ligase complex

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