The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior - PubMed (original) (raw)

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The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior

Yan Liu et al. Cell Cycle. 2009.

Abstract

In response to diverse stresses, the tumor suppressor p53 differentially regulates its target genes, variably inducing cell-cycle arrest, apoptosis or senescence. Emerging evidence indicates that p53 plays an important role in regulating hematopoietic stem cell (HSC) quiescence, self-renewal, apoptosis and aging. The p53 pathway is activated by DNA damage, defects in ribosome biogenesis, oxidative stress and oncogene induced p19 ARF upregulation. We present an overview of the current state of knowledge about p53 (and its target genes) in regulating HSC behavior, with the hope that understanding the molecular mechanisms that control p53 activity in HSCs and how p53 mutations affect its role in these events may facilitate the development of therapeutic strategies for eliminating leukemia (and cancer) propagating cells.

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Figure 1

Figure 1

p53 regulates hematopoietic stem cell behavior. (A) The role of p53 in steady state hematopoiesis. During steady state, p53 plays an important role in regulating both hematopoietic stem cell (HSC) quiescence and self-renewal. p53 normally maintains HSCs in a quiescent state, and in its absence, HSCs are driven into the cell cycle. The transcription factor MEF/ELF4 can directly regulate Mdm2 expression, thus MEF null mice have enhanced p53 activity. Loss of p53 in MEF/ELF4 null HSCs leads to normal HSC quiescence demonstrating that p53 is essential for the enhanced HSC quiescence seen in the absence of MEF. Both Gfi-1 and Necdin are p53 target genes and both function to restrict the proliferation of HSC. p53 has been shown to limit HSC self-renewal, yet how p53 regulates this process is unknown. (B) The role of p53 in stress hematopoiesis. In response to diverse stresses, p53 differentially regulates its target genes, variably inducing cell cycle arrest, apoptosis or senescence. p21 is a major target of p53 under stress conditions, and p21 has been implicated in cell cycle arrest, DNA damage repair and apoptosis. Slug is transcriptionally induced by p53 following irradiation and Slug protects the damaged cells from apoptosis by directly repressing p53-mediated activation of Puma gene expression. (C) The role of p53 in hematopoietic stem cell aging. p53 has been implicated in the aging process, as p53 hypermorphic (p53+/m) mice have higher p53 activity than wild-type mice, and display premature aging. However, “super-p53” mice, which have three copies of the wild type p53 gene, have a normal lifespan and show no evidence of early aging. It seems that the constitutively high p53 activity in the p53+/m mice accelerates aging, while the extra copy of p53 in the “super-p53” mice is subject to normal regulation, and may not lead to a change in p53 functional activity.

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