Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, Missouri, United States of America.
PLoS One. 2011 Jan 25;6(1):e15561. doi: 10.1371/journal.pone.0015561.
The CDC25 protein phosphatases drive cell cycle advancement by activating cyclin-dependent protein kinases (CDKs). Humans and mice encode three family members denoted CDC25A, -B and -C and genes encoding these family members can be disrupted individually with minimal phenotypic consequences in adult mice. However, adult mice globally deleted for all three phosphatases die within one week after Cdc25 disruption. A severe loss of absorptive villi due to a failure of crypt epithelial cells to proliferate was observed in the small intestines of these mice. Because the Cdc25s were globally deleted, the small intestinal phenotype and loss of animal viability could not be solely attributed to an intrinsic defect in the inability of small intestinal stem and progenitor cells to divide. Here, we report the consequences of deleting different combinations of Cdc25s specifically in intestinal epithelial cells. The phenotypes arising in these mice were then compared with those arising in mice globally deleted for the Cdc25s and in mice treated with irinotecan, a chemotherapeutic agent commonly used to treat colorectal cancer. We report that the phenotypes arising in mice globally deleted for the Cdc25s are due to the failure of small intestinal stem and progenitor cells to proliferate and that blocking cell division by inhibiting the cell cycle engine (through Cdc25 loss) versus by inducing DNA damage (via irinotecan) provokes a markedly different response of small intestinal epithelial cells. Finally, we demonstrate that CDC25A and CDC25B but not CDC25C compensate for each other to maintain the proliferative capacity of intestinal epithelial stem and progenitor cells.
CDC25 蛋白磷酸酶通过激活细胞周期依赖性蛋白激酶 (CDKs) 推动细胞周期前进。人类和小鼠分别编码三个家族成员，分别表示为 CDC25A、-B 和 -C，并且可以单独破坏这些家族成员的编码基因，而在成年小鼠中几乎没有表型后果。然而，所有三种磷酸酶在 Cdc25 破坏后一周内，成年小鼠会全球死亡。在这些小鼠的小肠中观察到由于隐窝上皮细胞不能增殖而导致吸收绒毛严重丧失。由于 Cdc25 被全局删除，因此小肠表型和动物活力丧失不能仅仅归因于小肠干细胞和祖细胞不能分裂的内在缺陷。在这里，我们报告了在肠上皮细胞中特异性删除不同组合的 Cdc25 的后果。然后将这些小鼠出现的表型与那些在 Cdc25 全局缺失的小鼠和用伊立替康治疗的小鼠（一种常用于治疗结直肠癌的化疗药物）出现的表型进行比较。我们报告说，在 Cdc25 全局缺失的小鼠中出现的表型是由于小肠干细胞和祖细胞不能增殖所致，而通过抑制细胞周期引擎（通过 Cdc25 缺失）而不是通过诱导 DNA 损伤（通过伊立替康）来阻止细胞分裂会引起小肠上皮细胞的反应明显不同。最后，我们证明 CDC25A 和 CDC25B 但不是 CDC25C 可以相互补偿，以维持肠上皮干细胞和祖细胞的增殖能力。
