Oleg N.Demidov1,2, Yunhua Zhu1, Calvina Kek1, Anastasia R. Goloudina2 , Noboru Motoyama3, Dmitry V. Bulavin1.
1 - Institute of Molecular and Cell Biology, Cell Cycle Control and Tumorigenesis Group, 61 Biopolis Drive, Proteos, Singapore 138673
2 - INSERM UMR 866, Faculty of Medicine and Pharmacy, University of Burgundy, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France
3 - Section of Molecular Aging, Department of Cognitive Brain Science Research Institute, National Center for Geriatrics and Gerontology 35, Gengo, Morioka, Obu Aichi 474-8511, Japan
Published in Cell Death and Differentiation, May 4, 2012
Conversion of intestinal stem cells into tumor-initiating cells is an early step in ApcMin-induced polyposis. Wip1-dependent activation of a DNA damage response and p53 plays a permanent role in suppression of stem cell conversion, and deletion of Wip1 lowers the tumor burden in ApcMin mice. Here we show that Cdkn2a, Chk2, and Gadd45a exert critical functions in the tumor-resistant phenotype of Wip1-deficient mice. We further identified Gadd45a as a haploinsufficient gene in the regulation of Wip1-dependent tumor resistance in mice. Gadd45a appears to function through its ability to activate the Jnk-dependent signaling pathway that in turn is a necessary mediator of the pro-apoptotic functions of p53 that respond to activation of the β-catenin signaling pathway. We propose that silencing of Gadd45a is sufficient to override p53 activation in the presence of active β-catenin under conditions of an enhanced DNA damage response.
Wip1 is required for survival of Lgr5-positive and Lgr5-negative, þ4 ISCs. (a) Analysis of apoptosis (red) using TUNEL staining and confocal microscopy was carried out in Wip1-deficient mice crossed with Lgr5-EGFP-IRES-creERT2 mice and treated with Gsk3 inhibitor IX. Two representative pictures of double positive (left image) and apoptosis-positive, Lgr5-negative cells (right image) are shown.
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