The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus

Abstract

The bmi-1 gene was first isolated as an oncogene that cooperates with c-myc in the generation of mouse lymphomas. We subsequently identified Bmi-1 as a transcriptional repressor belonging to the mouse Polycomb group. The Polycomb group comprises an important, conserved set of proteins that are required to maintain stable repression of specific target genes, such as homeobox-cluster genes, during development. In mice, the absence of bmi-1 expression results in neurological defects and severe proliferative defects in lymphoid cells, whereas bmi-1 overexpression induces lymphomas. Here we show that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence. In these fibroblasts and in bmi-1-deficient lymphocytes, the expression of the tumour suppressors p16 and p19Arf, which are encoded by ink4a, is raised markedly. Conversely, overexpression of bmi-1 allows fibroblast immortalization, downregulates expression of p16 and p19Arf and, in combination with H-ras, leads to neoplastic transformation. Removal of ink4a dramatically reduces the lymphoid and neurological defects seen in bmi-1-deficient mice, indicating that ink4a is a critical in vivo target for Bmi-1. Our results connect transcriptional repression by Polycomb-group proteins with cell-cycle control and senescence.

Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival

“…Furthermore, we recently reported that expression of exogenous Bmi-1 in NHOK led to significant extension (2.7 fold) of replicative life span but did not efficiently downregulate the expression of p16 INK4A (Kim et al, 2006). It is possible that Bmi-1 targets other important regulators of cell division in NHOK, such as p14 ARF or p15 INK4B , as previously suggested (Jacobs et al, 1999). Several recent studies also showed that the aberrant Bmi-1 expression is not necessarily associated with downregulation of p16 INK4A expression (Dukers et al, 2004;Breuer et al, 2005).…”

“…Bmi-1 protein was weakly detected in NHOK cultured in serum-free KGM and was not altered by the culture conditions (data not shown). As Bmi-1 is known to negatively regulate the expression of p16 INK4A in some cells (Jacobs et al, 1999), we checked for the correlation between the expression levels of Bmi-1 and p16 INK4A in our experimental system. Bmi-1 protein expression level was notably higher in most of the OSCC cell lines compared with that of NHOK, but did not correlate with the expression level of p16 INK4A , which correlated more closely with the human papillomavirus (HPV) infection status (Table 1).…”

“…Bmi-1 is one of the core subunits of the polycomb repressive complex 1, which regulates the diverse biological processes, including X chromosome inactivation, carcinogenesis, and stem cell renewal (Li et al, 2006;Sparmann and van Lohuizen, 2006). Cellular target genes of Bmi-1 have been identified and include ink4a and ink4b loci, encoding p16 INK4A , p19 ARF , and p15 INK4B (Jacobs et al, 1999). Bmi-1 is believed to promote cellular proliferation by repressing the expression of the ink4a locus, which plays pivotal roles in the onset of cellular senescence in many different types of human somatic cells (reviewed in Itahana et al, 2004).…”

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

“…After confirmation by restriction digestion and DNA sequencing, the sites introduced were used to allow domain exchange by standard recombinant techniques. These chimaeric HIF-a sequences were transferred into the retroviral vector pLZRS-IRES-GFP (Jacobs et al, 1999). Retroviral production and infection of target cells were conducted as previously described (Raval et al, 2005).…”

Aging, tumor suppression and cancer: high wire-act!

“…These events include DNA damage (DiLeonardo et al, 1994;Chen et al, 1995;Robles and Adami, 1998), as well as perturbations to chromatin organization (Ogryzko et al, 1996;Jacobs et al, 1999;Itahana et al, 2003;Narita et al, 2003). They also include the expression of certain oncogenes (Serrano et al, 1997;Zhu et al, 1998;Dimri et al, 2000) that deliver supraphysiological mitogenic signals to cells, and the overexpression of certain tumor suppressor genes (Sugrue et al, 1997;McConnell et al, 1998;Dai and Enders, 2000;Dimri et al, 2000;Beausejour et al, 2003).…”