title: Contributions made by CDC25 phosphatases to proliferation of intestinal epithelial stem and progenitor cells.
abstract: 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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Gwanghee
authors.initials: G
authors.lastname: Lee
authors.forename: Sofia
authors.initials: S
authors.lastname: Origanti
authors.forename: Lynn S
authors.initials: LS
authors.lastname: White
authors.forename: Jinwu
authors.initials: J
authors.lastname: Sun
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.forename: Helen
authors.initials: H
authors.lastname: Piwnica-Worms
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology*; D017353:Gene Deletion; D007421:Intestine, Small / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000502:physiology*
chemical_list: C517005:Cdc25a protein, mouse; C517006:Cdc25b protein, mouse; C517010:Cdc25c protein, mouse; D020687:cdc25 Phosphatases