Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion

被引:57
作者
Lee, Gwanghee [1 ]
White, Lynn S. [1 ,4 ]
Hurov, Kristen E. [1 ,4 ]
Stappenbeck, Thaddeus S. [2 ]
Piwnica-Worms, Helen [1 ,3 ,4 ]
机构
[1] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
CDC25; phosphatases; cell cycle; stem cells; STEM-CELLS; IN-VIVO; PHOSPHATASE; PROTEIN; MICE; DEPHOSPHORYLATION; PROLIFERATION; EXPRESSION; HOMOLOG; DIFFERENTIATION;
D O I
10.1073/pnas.0900751106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:4701 / 4706
页数:6
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