Key words Bmi 1 gene oncogene poly comb protein poly comb protein family self-renewing stem cell tumors occur
Stem cell self-renewal, multi-differentiation and unlimited proliferation ability. Malignancies fundamentally it is a stem cell disease, the root cause of the small number of stem cells to become malignant transformation, tumor recurrence and metastasis. Oncogene Bmi 1 can determine stem cell fate of: self-renewal or aging, and at the same time play an important role in tumorigenesis. In this paper, the oncogene Bmi 1 recent progress are reviewed.
1 Structure and Function
By oncogenic BMI-1 is located on human chromosome 10p11.23, the DNA of size 4.9kb, mRNA 3199bp, containing 10 exons, by 959 adenine, 591 cytosine, 678 guanine and 975 thymine encoding a protein of 326 amino acids, the molecular weight of 36.9 kDa, which Ploycomb histone (ploycomb group, PcG) family protein in the cytoplasm, chromatin or chromosomes [1,2]. Its NH2 terminus contains a conserved RF domain protein in the central region of H T H T conformation center, is the induction of telomerase activity and cellular immortalization epitopes [2,3].
The PCG family protein composition huge multimeric structure, modification of the chromatin, resulting in inhibition of gene expression or activation of these proteins interphase chromatin surface was concentrated, and the lack of internal chromatin was concentrated, so that the region of nuclear transcription of inhibition of [4 , 5]. The study confirmed the genetic outside PcG-mediated gene silencing is a local event, and will not affect the larger range chromatin regions , the central link in the regulation of gene expression is Bmi other little PcG proteins .
2 in stem cells, the role of
Bmi 1 by regulation such as survival genes, the antiproliferative gene stem cells genetically determined stem cell differentiation direction, regulation of hematopoietic stem cells (HSCs) self-renew. The Ink4a Bmi 1 downstream genes, encoding p16Ink4a and p14Arf enhanced expression induced senescence and apoptosis of HSCs . Neural stem cells the expressions of p16Ink4a the lack of Bmi 1 lack of stem cells to restore part of the self-renewal capacity . The possible mechanism of its regulation Bmi 1 lack p16Ink4a was lowered prevent Cdk4 / 6 and cyclin D combined with inhibition of kinase activity, pRB hyperphosphorylation, thereby inhibiting E2F-mediated transcription, cell cycle The pause, cellular senescence .
Normal mouse embryonic fibroblasts (MEFs) and cultured for 7 generations after aging, Bmi 1-/-MEFs third generation of immature aging p16Ink4a expression increases, re-expression of Bmi 1 can be reversed immature aging phenotype, while overexpression generated MEF proliferation advantage, extend its life and immortalized [10 12]. Mature HSCs p16Ink4a and p19Arf overexpression after pRB and p53-dependent pathway, induced cell cycle arrest and apoptosis. Studies have confirmed p16Ink4a, p19Arf and p53 Bmi 1 downstream factor involved in the control of the proliferation and survival of HSCs during stem cell differentiation. Bmi 1 through the inhibition of some genes involved in cell senescence maintain HSC pool. In Bmi 1 – / – bone marrow p53 target genes Wig1 from increased expression, suggesting that p19Arf pathway is activated in Bmi 1 – / – hematopoietic cells [5,6,9].
HSCs and neural stem cells express high levels of Bmi 1, lack of Bmi 1 mice after birth in hematopoietic constituent of bone, nervous system function and cerebellar development on both defects [4,5,7,8]. By transplantation Bmi-1 – / – fetal liver cells to produce temporary hematopoietic reconstitution, to increase the number of pluripotent progenitor cells, without increasing the number of HSCs, lasted only 4 to 8 weeks of hematopoiesis. Lack of Bmi 1 of the neural stem cell self-renewal reducing postnatal stem cell depletion and developmental defects in the peripheral and central nervous system, but before the progenitor cells of the survival period and proliferation ability basically normal, prove Bmi 1 is maintaining the neural stem cell number of key factors [7, 13].
3 in tumor
Bmi 1 may play a key role in the incidence of malignant tumors. Overexpression of Bmi 1 can up-regulate the transcription of the human telomere reverse transcriptase (hTERT), increased telomerase activity and prevent cell aging, immortalized, play an important role in the malignant transformation of cells . Bmi 1 overexpression lead to mammary epithelial cells (MECs) malignant transformation and immortalization, clonal selection process of malignant transformation, p16Ink4a increasingly silent gene, telomerase activity gradually increased [3,13].
Mantle cell lymphoma cells Bmi 1 DNA amplification and protein expression 3-7 times higher than the normal cells, while mice with acute myeloid leukemia stem cells could be detected in high levels of Bmi 1 transcription shows Bmi 1 in the blood system an important role in tumorigenesis [14, 15]. In solid tumors, Vonlanthen  and other observed 48 patients with resectable NSCLC Bmi 1 expression, immunohistochemistry 20,22,6 cases expressed as negative / weak, moderate and strong positive intensity of Bmi 1 stained specimens were negative, p16 and p14ARF high level of Bmi 1 protein expression in 58% of NSCLC. Another research group  found that 69% of bronchial squamous cell carcinoma low p16 expression, the expression of 77% of the two cases in the the Bmi 1,4 patients with p16 positive Bmi 1 positive, 8 cases (89 in 9 patients with p16-negative specimens %) Bmi 1 positive staining, 4 patients with p16-negative specimens in p16INK4a hypermethylation of the promoter region, other negative specimens without methylation, but Bmi 1 staining, Bmi 1 onwards in the incidence of lung cancer are certain role. Recent studies show that Bmi 1 mRNA levels in colorectal cancer than paracancerous organizations significantly increased protein expression (or high) in 65% (30/46) of colorectal cancer, Bmi 1 high expression organization INK4 protein was significantly lower expression (P <0.07), that Bmi 1 by inhibiting INK4a/ARF proteins involved in colorectal cancer . 33 cases of breast cancer specimens RT PCR analysis showed that 28 specimens Bmi 1 mRNA level was higher than the adjacent tissues and immunohistochemistry showed that the 44/77 (62%) of primary invasive breast cancer tissue stained strongly positive And the peripheral infiltrates parts is higher than the staining intensity of the tumor center. Multivariate and univariate analysis showed Bmi 1 expression and axillary lymph node metastasis and ER receptor status were significantly correlated .
Bmi 1 through inhibition of genes involved in the aging and (or) may prevent the shortening of telomeres by inducing telomerase to prevent immature aging to maintain the stem cell pool. Because it is the expression of a wide range of Bmi 1 may maintain the stem cells of various types of entities is extremely important, can be used as molecular markers of cancer stem cell expansion, blocking Bmi 1 induced stem cell expansion can terminate stem cell expansion “lifeline become the target genes of cancer treatment. Further determine Bmi 1 in stem cells, especially in the cancer stem cell regulation mechanisms, and its role in the occurrence and recurrence of the tumor may be important for the treatment of malignant tumors.