Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis.

Cell Death and Differentiation
Oleg N DemidovDmitry V Bulavin

Abstract

Conversion of intestinal stem cells into tumor-initiating cells is an early step in Apc(Min)-induced polyposis. Wild-type p53-induced phosphatase 1 (Wip1)-dependent activation of a DNA damage response and p53 has 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 cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and growth arrest and DNA damage gene 45a (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 proapoptotic 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.

References

Oct 18, 1996·Cell·K W Kinzler, B Vogelstein
Nov 2, 2001·Nature·T ReyaI L Weissman
May 22, 2002·Nature Genetics·Dmitry V BulavinEttore Appella
Oct 3, 2002·The EMBO Journal·Hiroyuki TakaiNoboru Motoyama
Jan 23, 2004·Nature Reviews. Cancer·Ricardo PardalSean J Morrison
Jun 17, 2004·Genes & Development·Owen J SansomDouglas J Winton
Apr 15, 2005·Nature·Tannishtha Reya, Hans Clevers
Oct 27, 2005·British Journal of Cancer·B P NutleyF I Raynaud
Nov 29, 2005·Cell Death and Differentiation·H FujimotoY Minami
Jan 5, 2006·Genes & Development·Susan M MendrysaMary Ellen Perry
Apr 11, 2006·Molecular Cell·Dos D SarbassovDavid M Sabatini
Sep 5, 2006·Molecular Cell·Sathyavageeswaran ShreeramDmitry V Bulavin
Dec 13, 2006·The Journal of Experimental Medicine·Sathyavageeswaran ShreeramDmitry V Bulavin
Feb 27, 2007·Oncogene·H F Horn, K H Vousden
Apr 26, 2007·Cell Cycle·Alejo Efeyan, Manuel Serrano
Jun 10, 2008·Nature Genetics·Eugenio Sangiorgi, Mario R Capecchi
Oct 29, 2008·Oncogene·E C PietschM E Murphy
Dec 19, 2008·Nature·Nick BarkerHans Clevers
Jul 22, 2009·Developmental Cell·Esther Sook Miin WongDmitry V Bulavin
Feb 15, 2011·Nature Genetics·Daniel SchramekJosef M Penninger

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adenomatous Polyposis Coli

Adenomatous polyposis coli is a protein encoded by the APC gene and acts as a tumor suppressor. Discover the latest research on adenomatous polyposis coli here.