p38MAPK Controls Expression of Multiple Cell Cycle Inhibitors and Islet Proliferation with Advancing Age Esther Sook Miin Wong, Xavier Le Guezennec, Oleg N. Demidov, Nicolette Theresa Marshall, Siew Tein Wang, Janakiraman Krishnamurthy, Norman E. Sharpless, N. Ray Dunn, Dmitry V. Bulavin Developmental Cell - 21 July 2009 (Vol. 17, Issue 1, pp. 142-149)
Abstract:
Aging is a complex organismal process that is controlled by genetic, environmental, and behavioral factors. Accumulating evidence supports a role for different cell cycle inhibitors in mammalian aging. Little is known, however, about the upstream signals that induce their expression. Here, we explore the role of p38MAPK by generating a dominant-negative allele (p38AF) in which activating phosphorylation sites Thr180 and Tyr182 are mutated. Heterozygous p38AF mice show a marked attenuation of p38-dependent signaling and age-induced expression of multiple cell cycle inhibitors in different organs, including pancreatic islets. As a result, aged p38AF/+ mice show enhanced proliferation and regeneration of islets when compared to wild-type littermates. We further find an age-related reduction in expression of the p38-specific phosphatase Wip1. Wip1-deficient mice demonstrate decreased islet proliferation, while Wip1 overexpression rescues aging-related decline in proliferation and regenerative capacity. We propose that modulation of p38MAPK activity may provide new avenues for treating certain age-related degenerative diseases.
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