Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways
Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways
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DOI：
10.1038/ncomms7808
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发表时间：
2015-04-01
影响因子：
16.6
通讯作者：
Ju, Zhenyu
中科院分区：
文献类型：
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作者：
Chen, Zhiyang;Yi, Weiwei;Ju, Zhenyu
野生型p53诱导的磷酸酶1（Wip 1）负调节几个肿瘤抑制和DNA损伤反应途径。然而，Wip 1对造血干细胞（HSC）稳态和衰老的影响仍然未知。在这里，我们发现Wip 1在HSC中高度表达，但随着年龄的增长而减少。Wip 1缺陷（Wip 1（-/-））小鼠表现出多方面的HSC老化表型，包括池大小增加和重建活动受损。p53的缺失挽救了Wip 1（-/-）HSC的多谱系再增殖缺陷，而不影响细胞衰老或凋亡，表明Wip 1-p53轴以独立于常规p53途径的方式调节HSC分化。然而，在Wip 1（-/-）小鼠中，p53缺失并不影响HSC池大小的增加。有趣的是，在Wip 1（-/-）小鼠中HSC的扩增是由于mTORC 1介导的HSC增殖。因此，我们的研究揭示了干细胞衰老的机制，其中p53和mTORC 1通路对HSC衰老的不同影响由Wip 1控制。
Wild-type p53-induced phosphatase 1 (Wip1) negatively regulates several tumour suppressor and DNA damage response pathways. However, the impact of Wip1 on haematopoietic stem cell (HSC) homeostasis and aging remains unknown. Here we show that Wip1 is highly expressed in HSCs but decreases with age. Wip1-deficient (Wip1(-/-)) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity. Deletion of p53 rescued the multilineage repopulation defect of Wip1(-/-) HSCs without affecting cellular senescence or apoptosis, indicating that the Wip1-p53 axis regulates HSC differentiation in a manner independent of conventional p53 pathways. However, p53 deletion did not influence the increased HSC pool size in Wip1(-/-) mice. Interestingly, the expansion of HSCs in Wip1(-/-) mice was due to an mTORC1-mediated HSC proliferation. Thus, our study reveals a mechanism of stem cell aging, in which distinct effects of p53 and mTORC1 pathways on HSC aging are governed by Wip1.