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.

Repression of Cyclin D1 Expression Is Necessary for the Maintenance of Cell Cycle Exit in Adult Mammalian Cardiomyocytes

“…4). In addition, conditional knock-out (KO) experiments of single, double, and triple Cdc25 subtypes revealed that only triple and double (Cdc25a and -b) KO mice show robust phenotypes in intestinal epithelial cells, such as the inhibition of mitosis (30,31). These reports indi-5 S. Ogawa, M. Kubota, and T. Takeuchi, unpublished data.…”

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

“…We previously reported a loss of villus goblet cells and an increase in acute inflammatory cells in the SI of irinotecan-treated mice (14). To determine if fasting before chemotherapy protected against this proinflammatory response, fed and fasted mice (Lgr5 reporter strain) were treated with 80 mg/kg etoposide ( Fig.…”

Involvement of Cdc25c in Cell Cycle Alteration of a Radioresistant Lung Cancer Cell Line Established with Fractionated Ionizing Radiation

“…Lim et al have proved that cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and may be suitable targets for therapy (Lim et al, 2012). The cell cycle division cycle 25 (Cdc25) protein phosphates, including three family proteins, Cdc25a, Cdc25b, Cdc25c, are critical components of cell engine that function to drive cell cycle transitions by dephosphorylating and activating cyclin-dependent kinases (Cdks) (Lee et al, 2011). Cdc25a is the master regulator of the G1-S transition, S-phase transition and G2-M progression, whereas Cdc25b and Cdc25c have more restricted roles in G2-M progression (Iliakis et al, 2003).…”