Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16^Ink4a and p19^Arf senescence pathways

Abstract

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Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

“…These findings indicate that Ink4a/Arf is the major target of Bmi1 in hepatic stem cells as in HSCs and NSCs. 11,12 Bmi1 is also essential for cancer stem cells as demonstrated in a mouse leukemia model as well as in a mouse lung tumor model generated by the expression of a mutant K-ras gene in bronchioalveolar stem cells. 5,26 In addition, we previously demonstrated that forced expression of Bmi1 promotes the self-renewal of hepatic stem/progenitor cells and contributes to malignant transformation.…”

“…10,11 Deletion of Ink4a/Arf similarly rescues neural stem cell (NSC) selfrenewal and frequencies in Bmi1-deficient mice, although its effect is reportedly partial. 12 In the oncogenic setting, the Ink4a-retinoblastoma protein (Rb) and Arf-p53 cellular senescence pathways trigger oncogene-induced senescence to eliminate transforming cells that potentially develop into cancer stem cells. 2 Given that enhanced expression of BMI1 and reduced expression of INK4A/ARF are frequently observed in human hepatocellular carcinoma (HCC) samples, 13,14 it would be of importance to understand the contribution of the Ink4a/Arf locus to the oncogenic functions of Bmi1 in cancer and search for as-yet-unknown target genes of Bmi1 other than Ink4a/Arf.…”

Epigenetic regulation of aging stem cells

“…Deletion of the entire p16 INK4a /p19 ARF locus, but not that of p19 ARF alone, can mostly rescue the effect of Bmi1 deficiency on HSC self-renewal in long-term competitive repopulation assays (Oguro et al, 2006). p19 ARF may be a more critical target in adult NSCs, as p19 ARF deletion partially rescues self-renewal defects caused by Bmi1 deficiency, although to a lesser extent than deletion of the entire p16 INK4a / p19 ARF locus (Bruggeman et al, 2005;Molofsky et al, 2005). In contrast to chronic Bmi1 loss, acute RNA interference-mediated knockdown of Bmi1 in NSC cultures from young adult mice does not lead to an increase in p16 INK4a or p19 ARF expression, but results in altered expression of another cell cycle inhibitor, p21 CIP1 , which can rescue the antiproliferative phenotype of Bmi1 knockdown (Fasano et al, 2007).…”

“…Furthermore, BMI1 plays a non-cell autonomous role in the bone marrow microenvironment that does not depend on p16 INK4a or p19 ARF (Oguro et al, 2006). Similarly, deletion of the entire p16 INK4a /p19 ARF locus in Bmi1 À/À mice does not completely rescue NSC defects in selfrenewal capacity (Bruggeman et al, 2005;Molofsky et al, 2005).…”

Attributes of adult stem cells

“…The premature senescence of murine neural stem cells is prevented by Bmi1, suppressing transcription at the Ink4a-Arf locus that encodes p16 Ink 4a and p19 Arf [62]. In the mouse small intestine, Bmi1-expressing cells can be localized by in situ hybridization as being located at cell position 4-5, counting from the bottom of the crypt, and lineage tracing from Bmi1-expressing cells suggests that these cells can also generate long-lived clones containing all the intestinal cell lineages [63].…”