Regulation of cell cycle, apoptosis, and senescence by Bmi1. In normal stem cells, p16Ink4a and p19Arf genes are repressed in a Bmi1-dependent manner. In the absence of p16Ink4a, the cyclin D/Cdk4/6 complex can phosphorylate pRB, allowing the E2F-dependent transcription that leads to cell cycle progression and DNA synthesis. In addition, MDM2-mediated p53 degradation causes low p53 levels in the absence of p19Arf, thus preventing cell cycle arrest and apoptosis. The absence of Bmi1 relieves the repression of the Ink4a locus, resulting in the expression of p16Ink4a and p19Arf. p16Ink4a inhibits binding of cyclin D to Cdk4/6, resulting in inhibition of the kinase activity. This leads to a hypophosphorylated pRB, which then can bind E2F and inhibit E2F-dependent transcription, resulting in cell cycle arrest and senescence. p19Arf inhibits MDM2, which mediates ubiquitin-dependent degradation of p53, thus leading to accumulation of p53 protein in the cell. This leads to induction of various p53 target genes involved in cell cycle arrest and apoptosis. Proteins affected by high and low levels of Bmi1 are shown by black and red arrows, respectively. *Sites of frequent mutations associated with cancer.