A small molecule inhibitor of p53 stimulates amplification of hematopoietic stem cells but does not promote tumor development in mice.
A small molecule inhibitor of p53 stimulates amplification of hematopoietic stem cells but does not promote tumor development in mice.
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DOI：
10.4161/cc.9.7.11508
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发表时间：
2010-04-01
期刊：
影响因子：
--
通讯作者：
Gudkov AV
中科院分区：
文献类型：
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作者：
Leonova KI;Shneyder J;Antoch MP;Toshkov IA;Novototskaya LR;Komarov PG;Komarova EA;Gudkov AV
研究表明，p53 的基因抑制可增强造血干细胞 (HSC) 的增殖。从理论上讲，这可能导致 p53 缺陷小鼠和人类中观察到的肿瘤发生频率增加。在我们之前的工作中，我们发现了化学 p53 抑制剂 (PFT)，可以抑制 p53 的反式激活功能，并保护培养细胞和小鼠免受伽马射线 (IR) 诱导的死亡。在这里，我们发现，当应用于体外骨髓细胞或注射到小鼠体内时，PFTβ 可以阻止 IR 诱导的造血干细胞 (HSC) 和造血祖细胞 (HPC) 群体规模的减少。此外，我们还发现，在体外和体内没有IR的情况下，PFTβ可刺激HSC和HPC增殖，并将HSC动员至外周血。然而，重要的是，PFTβ治疗并不影响用作确定致癌性模型的受辐射p53杂合小鼠中肿瘤发生的时间或频率。因此，尽管 PFTβ 给药导致 HSC 和 HPC 数量增加，但它对小鼠并不致癌。这些发现表明化学 p53 抑制剂可能在临床上作为安全有效的造血刺激剂有用。
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-defcient 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, PFTβ impeded IR-induced reduction of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) population sizes. In addition, we showed that PFTβ stimulated HSC and HPC proliferation in the absence of IR in vitro and in vivo and mobilized HSCs to the peripheral blood. Importantly, however, PFTβ 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 PFTβ 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.