p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age.
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 (p38(AF)) in which activating phosphorylation sites Thr180 and Tyr182 are mutated. Heterozygous p38(AF) 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 p38(AF/+) 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.
Wong
Esther Sook Miin
ES
Institute of Molecular and Cell Biology, Proteos, Singapore.
Le Guezennec
Xavier
X
Demidov
Oleg N
ON
Marshall
Nicolette Theresa
NT
Wang
Siew Tein
ST
Krishnamurthy
Janakiraman
J
Sharpless
Norman E
NE
Dunn
N Ray
NR
Bulavin
Dmitry V
DV
D000375:Aging / Q000502:physiology*; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D012097:Repressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C