Article

p53 Regulates Hematopoietic Stem Cell Quiescence

Molecular Phamacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cell stem cell (Impact Factor: 22.15). 02/2009; 4(1):37-48. DOI: 10.1016/j.stem.2008.11.006
Source: PubMed

ABSTRACT The importance of the p53 protein in the cellular response to DNA damage is well known, but its function during steady-state hematopoiesis has not been established. We have defined a critical role of p53 in regulating hematopoietic stem cell quiescence, especially in promoting the enhanced quiescence seen in HSCs that lack the MEF/ELF4 transcription factor. Transcription profiling of HSCs isolated from wild-type and p53 null mice identified Gfi-1 and Necdin as p53 target genes, and using lentiviral vectors to upregulate or knockdown the expression of these genes, we show their importance in regulating HSC quiescence. Establishing the role of p53 (and its target genes) in controlling the cell-cycle entry of HSCs may lead to therapeutic strategies capable of eliminating quiescent cancer (stem) cells.

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    • "First, CML arises from a normal pluripotent stem cell, which lacks expression of relevant functional levels of p53, because in stem cells, p53 negatively regulates self-renewability, quiescence [62–65] and pluripotency by reprogramming [66]. Secondly, polycomb repressor complexes epigenetically silence the Cdkn2a/b gene cluster (encoding INK-4A/ARF) in hematopoietic stem cells. "
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    • "HSCs in old mice lacking p16 have increased regenerative potential, suggesting that p16 plays a critical role in limiting HSC selfrenewal (Janzen et al., 2006). In p53-null mice, the number of HSCs increases and they perform better in competitive repopulation, suggesting an enhanced self-renewal capacity (TeKippe et al., 2003; Liu et al., 2009). Moreover, mice with one wild-type allele and one mutant allele of p53 that lacks the N-terminal transactivation domain maintain cancer protection, but age prematurely including impairment of HSCs (Tyner et al., 2002; Maier et al., 2004; Dumble et al., 2007). "
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