Figure 2.

Regulation of cell cycle, apoptosis, and senescence by self-renewal factor Bmi1. Bmi1, a component of PRC1, is involved in the stem cell maintenance in multiple tissues and organs. PRC1 suppresses the Ink4a locus that encodes the p16^Ink4a and the p19^Arf genes through the specific biochemical histone modifications, such as the trimethylation of the H3-K27 (H3K27me3) and the ubiquitination of H2A-K119 (H2AK119Ub). The chromodomain of CBX binds to H3K27me3 and RING1 deposits monoubiquitin on H2AK119. In the absence of p16^Ink4a, the cyclin D/Cdk4/6 complex can phosphorylate RB, allowing the E2F-dependent transcription which leads to cell cycle progression. In the absence of p19^Arf, MDM2-mediated p53 degradation causes low p53 levels, thus preventing cell cycle arrest and apoptosis. In addition, the gradual accumulation of p16^Ink4a expression during physiological aging implicates that p16^Ink4a is involved in the regulation of senescence.