Bmi1, stem cells, and senescence regulation

Abstract

Stem cells generate the differentiated cell types within many organs throughout the lifespan of an organism and are thus ultimately responsible for the longevity of multicellular organisms. Therefore, senescence of stem cells must be prevented. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death.

Figure 1

Postulated Bmi1 targets. Extrinsic signals for a stem cell to self-renew result in elevation of the Bmi1 level in stem cells. This allows repression of various genes including the Ink4a locus genes, p16Ink4a and p19Arf, and possibly activation, via indirect mechanisms, of some genes including telomerase, apoptosis inhibitor-6 (Ai6), and platelet-activating factor acetylhydrolase (PAF-AHγ). These genes are likely play a role in stem cell fate decisions including self-renewal and differentiation. *Sites of frequent mutations associated with cancer. TJP, tight junction protein. RDC1, chemokine orphan receptor 1.

Figure 2

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.