Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine
Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine
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DOI：
10.1016/j.stem.2007.05.020
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发表时间：
2007-08-01
期刊：
影响因子：
23.9
通讯作者：
Bulavin, Dmitry V.
中科院分区：
文献类型：
--
作者：
Demidov, Oleg N.;Timofeev, Oleg;Bulavin, Dmitry V.
结直肠癌是癌症相关死亡的主要原因之一。为了进一步了解其发展的机制，我们研究了Wip1磷酸酶在APC（Min）驱动的息肉病小鼠模型中的作用。Wip1磷酸酶在肠干细胞中高度表达。我们发现，去除Wip1通过显著抑制息肉形成，延长了APC（Min）小鼠的寿命。这种保护作用依赖于p53肿瘤抑制因子，而p53在肠干细胞凋亡的调控中起着假定的作用。当Wnt通路被组成性激活时，wip1缺陷小鼠（而非野生型APC（Min）小鼠）干细胞的凋亡激活增加。因此，我们提出Wip1磷酸酶调节肠道干细胞的内稳态。反过来，Wip1缺失通过降低p53依赖性干细胞凋亡的阈值来抑制APC（Min）驱动的息肉病，从而阻止它们转化为肿瘤启动干细胞。
Colorectal cancer is one of the major causes of cancer-related deaths. To gain further insights into the mechanisms underlying its development, we investigated the role of Wip1 phosphatase, which is highly expressed in intestinal stem cells, in the mouse model of APC(Min)-driven polyposis. We found that Wip1 removal increased the life span of APC(Min) mice through a significant suppression of polyp formation. This protection was dependent on the p53 tumor suppressor, which plays a putative role in the regulation of apoptosis of intestinal stem cells. Activation of apoptosis in stem cells of Wip1-deficient mice, but not wild-type APC(Min) mice, increased when the Wnt pathway was constitutively activated. We propose, therefore, that the Wip1 phosphatase regulates homeostasis of intestinal stem cells. In turn, Wip1 loss suppresses APC(Min)-driven polyposis by lowering the threshold for p53-dependent apoptosis of stem cells, thus preventing their conversion into tumor-initiating stem cells.