Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion
Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion
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DOI：
10.1073/pnas.0900751106
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发表时间：
2009-03-24
影响因子：
11.1
通讯作者：
Piwnica-Worms, Helen
中科院分区：
文献类型：
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作者：
Lee, Gwanghee;White, Lynn S.;Piwnica-Worms, Helen
CDC25蛋白磷酸酶（CDC25A、B和C）通过激活细胞周期引擎的关键组分来驱动细胞周期转换。CDC25A和CDC25B在人类癌症中经常过度产生。单独或联合破坏Cdc25B或Cdc25C对小鼠的生存能力没有影响。在此我们报道，CDC25A是在早期胚胎发育过程中提供关键功能的唯一家族成员，并且其他家族成员在成年小鼠中弥补了它的缺失。相反，由于在利贝昆氏隐窝中小肠上皮细胞增殖的丧失，整个家族的条件性破坏在成年小鼠中是致命的。Cdc25缺失诱导Wnt信号传导，并且整个隐窝结构得以保留。在持续的Wnt信号传导情况下，几乎所有隐窝上皮祖细胞分化为多种细胞谱系，包括隐窝基底柱状细胞，一种被认为是干细胞的细胞。在这些隐窝中保留了一小部分Musashi/Dcamkl - 1/核β - 连环蛋白阳性上皮细胞。这些发现对开发特异性针对细胞周期的新型、细胞毒性更小的癌症化疗药物具有启示意义。
The CDC25 protein phosphatases (CDC25A, B, and C) drive cell cycle transitions by activating key components of the cell cycle engine. CDC25A and CDC25B are frequently overproduced in human cancers. Disruption of Cdc25B or Cdc25C individually or in combination has no effect on mouse viability. Here we report that CDC25A is the only family member to provide an essential function during early embryonic development, and that other family members compensate for its loss in adult mice. In contrast, conditional disruption of the entire family is lethal in adults due to a loss of small intestinal epithelial cell proliferation in crypts of Lieberkuhn. Cdc25 loss induced Wnt signaling, and overall crypt structures were preserved. In the face of continuous Wnt signaling, nearly all crypt epithelial progenitors differentiated into multiple cell lineages, including crypt base columnar cells, a proposed stem cell. A small population of Musashi/Dcamkl-1/nuclear beta-catenin-positive epithelial cells was retained in these crypts. These findings have implications for the development of novel, less cytotoxic cancer chemotherapeutic drugs that specifically target the cell cycle.