Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion.
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 Lieberkühn. 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.
Lee
Gwanghee
G
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
White
Lynn S
LS
Hurov
Kristen E
KE
Stappenbeck
Thaddeus S
TS
Piwnica-Worms
Helen
H
D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000201:enzymology; D002455:Cell Division; D002478:Cells, Cultured; D003433:Crosses, Genetic; D047108:Embryonic Development; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology* / Q000648:ultrastructure; D005260:Female; D016193:G1 Phase; D016195:G2 Phase; D017353:Gene Deletion; D005838:Genotype; D006706:Homeostasis; D007421:Intestine, Small / Q000166:cytology* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020687:cdc25 Phosphatases / Q000172:deficiency*
C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases