Authors
Oleg N.Demidov^1,2, 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

Abstract

Conversion of intestinal stem cells into tumor-initiating cells is an early step in Apc^Min-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 Apc^Min 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.

Figure Legend:
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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