Journal
STEM CELLS
Volume 31, Issue 1, Pages 190-202Publisher
WILEY-BLACKWELL
DOI: 10.1002/stem.1274
Keywords
Bmi1; Survivin; Oxidative stress; DNA damage; Neural stem cells; Glioma
Categories
Funding
- Medical Research Council U.K. [G0800020, 85704]
- Cancer Research Fund [442/1289]
- Barts and The London Charity
- National Hospital Development Foundation, UCL ION
- NIHR Comprehensive Biomedical Research Centre [CBRC 31]
- Samantha Dickson Brain Tumor Trust [SDBTT 0805]
- MRC [G0800020] Funding Source: UKRI
- Ataxia UK [7196, 7195] Funding Source: researchfish
- Medical Research Council [G0800020] Funding Source: researchfish
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Polycomb group proteins are essential regulators of stem cell function during embryonic development and in adult tissue homeostasis. Bmi1, a key component of the Polycomb Repressive Complex 1, is highly expressed in undifferentiated neural stem cells (NSC) as well as in several human cancers including high-grade gliomas-highly aggressive brain tumors. Using a conditional gene activation approach in mice, we show that overexpression of Bmi1 induces repressive epigenetic regulation of the promoter of Survivin, a well-characterized antiapoptotic protein. This phenomenon is cell type-specific and it leads to apoptotic death of progenitor cells exclusively upon commitment toward a neuronal fate. Moreover, we show that this is triggered by increased oxidative stress-induced DNA damage. In contrast, undifferentiated NSC as well as glioma-initiating cells display an open chromatin configuration at the Survivin promoter and do not undergo apoptotic death. These findings raise the possibility that normal and neoplastic stem cells depend on the same mechanism for surviving the hyperproliferative state induced by increased Bmi1 expression. STEM CELLS 2013;31:190-202
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