期刊
CELL CYCLE
卷 9, 期 7, 页码 1434-1443出版社
LANDES BIOSCIENCE
DOI: 10.4161/cc.9.7.11508
关键词
p53 inhibitor; hematopoietic stem cells; cancer; lymphoma; sarcoma; radiation
类别
资金
- NCI NIH HHS [R01 CA075179, CA75179] Funding Source: Medline
- NIGMS NIH HHS [R01 GM075226, GM075226] Funding Source: Medline
It has been shown that genetic inhibition of p53 leads to enhanced proliferation of hematopoietic stem cells (HSCs). This could, in theory, contribute to the increased frequency of tumor development observed in p53-deficient mice and humans. In our previous work, we identified chemical p53 inhibitors (PFTs) that suppress the transactivation function of p53 and protect cultured cells and mice from death induced by gamma irradiation (IR). here we found that when applied to bone marrow cells in vitro or injected into mice, PFT beta impeded IR-induced reduction of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) population sizes. In addition, we showed that PFT beta stimulated HSC and HPC proliferation in the absence of IR in vitro and in vivo and mobilized HSCs to the peripheral blood. Importantly, however, PFT beta treatment did not affect the timing or frequency of tumor development in irradiated p53 heterozygous mice used as a model for determination of carcinogenicity. Thus, although PFT beta administration led to increased numbers of HSCs and HPCs, it was not carcinogenic in mice. These findings suggest that chemical p53 inhibitors may be clinically useful as safe and effective stimulators of hematopoiesis.
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