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). [3] [4] BMI1 is a polycomb ring finger oncogene.
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 that BMI1 is rapidly recruited to sites of DNA damage, where it sustains for over 8h. Loss of BMI1 leads to radiation sensitive and impaired repair of DNA double-strand breaks by homologous recombination. [5]
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. [6] [7] 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. [8]
Bmi1 is also thought to inhibit ageing in neurons through the suppression of p53. [9]
The Bmi-1 protein interacts with several signaling pathways containing Wnt, Akt, Notch, Hedgehog and receptor tyrosine kinases (RTK). In Ewing sarcoma family of tumors (ESFT), the knockdown of BMI-1 gene would greatly influence the Notch and Wnt signaling pathway which are important for ESFT formation and development. [10] Bmi-1 was shown to mediate the effect of Hedgehog signaling pathway on mammary stem cell proliferation. [11] Bmi-1 also regulates multiple downstream factors or genes. It represses p19Arf and p16Ink4a. Bmi-1-/- neural stem cells and HSCs have high expression level of p19Arf and p16Ink4a which diminished the proliferation rate. [12] [13] Bmi-1 is also indicated as a key factor in controlling Th2 cell differentiation and development by stabilizing GATA transcription factors. [14]
The BMI-1 gene is 10.04 kb with 10 exon and is highly conserved sequence between species. The human BMI-1 gene localizes at chromosome 10 (10p11.23). The Bmi-1 protein is consist of 326 amino acids and has a molecular weight of 36949 Da. Bmi1 has a RING finger at the N-terminus and a central helix-turn-helix domain. [15] The ring finger domain is a cysteine rich domain (CRD) involved in zinc binding and contributes to the ubiquitination process. The binding of bmi-1 to Ring 1B would activate the E3 ubiquitin ligase activity greatly. It is indicated that both the RING domain and the extended N-terminal tail contribute to the interaction of bmi-1 and Ring 1B. [16]
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. [17] Inhibiting BMI1 has been shown to inhibit the proliferation of glioblastoma multiforme, [18] chemoresistant ovarian cancer, prostatic, pancreatic and skin cancers. [4] Colorectal cancer stem cell self-renewal was reduced by BMI1 inhibition. The colon cancer stem cells in mouse xenografts could be eliminated by inhibiting BMI-1 gene, providing a novel potential method to treat colorectal cancer. [19]
According to a study by Canadian doctors, the loss of the BMI1 gene expression in human neurons may play a direct role in the development of Alzheimer's disease. [20] [21]
BMI1 has been shown to interact with:
Polycomb-group proteins are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies. They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.
Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.
Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ATF6 gene and is involved in the unfolded protein response.
C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the CTBP1 gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2.
Zinc phosphodiesterase ELAC protein 2 is an enzyme that in humans is encoded by the ELAC2 gene. on chromosome 17. It is an endonuclease thought to be involved in mitochondrial tRNA maturation,
HIV Tat-specific factor 1 is a protein that in humans is encoded by the HTATSF1 gene.
E3 ubiquitin-protein ligase RING2 is an enzyme that in humans is encoded by the RNF2 gene.
Polycomb protein EED is a protein that in humans is encoded by the EED gene.
C-terminal-binding protein 2 also known as CtBP2 is a protein that in humans is encoded by the CTBP2 gene.
E3 ubiquitin-protein ligase RING1 is an enzyme that in humans is encoded by the RING1 gene.
Polyhomeotic-like protein 1 is a protein that in humans is encoded by the PHC1 gene.
Polycomb group RING finger protein 2, PCGF2, also known as MEL18 or RNF110, is a protein that in humans is encoded by the PCGF2 gene.
MAP kinase-activated protein kinase 3 is an enzyme that in humans is encoded by the MAPKAPK3 gene.
Polyhomeotic-like protein 2 is a protein that in humans is encoded by the PHC2 gene.
Histone-lysine N-methyltransferase EZH1 is an enzyme that in humans is encoded by the EZH1 gene.
Chromobox protein homolog 8 is a protein that in humans is encoded by the CBX8 gene.
Krüppel-like factor 3 is a protein that in humans is encoded by the KLF3 gene.
Polycomb group RING finger protein 1, PCGF1, also known as NSPC1 or RNF68 is a RING finger domain protein that in humans is encoded by the PCGF1 gene.
Bithoraxoid (bxd) is a long non-coding RNA found in Drosophila. It silences the expression of the Ultrabithorax (Ubx) gene by transcriptional interference.
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