WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) delays cellular senescence by promoting p27 Kip1 degradation in human diploid fibroblasts

Abstract

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) plays an important role in the proliferation of tumor cells and the lifespan of Caenorhabditis elegans. However, the role of WWP1 in cellular senescence is still unknown. Here, we show that the expression patterns of p27 Kip1 and WWP1 are inversely correlated during cellular senescence. Moreover, the overexpression of WWP1 delayed senescence, whereas the knockdown of WWP1 led to premature senescence in human fibroblasts. Furthermore, we demonstrate that WWP1 repressed endogenous p27 Kip1 expression through ubiquitin- proteasome-mediated degradation. Additionally, WWP1 had a strong preference for catalyzing the Lys-48-linked polyubiquitination of p27 Kip1 in vitro. Finally, we demonstrate that WWP1 markedly inhibited the replicative senescence induced by p27 Kip1 by promoting p27 Kip1 degradation. Therefore, our study provides a new molecular mechanism for the regulation of cellular senescence. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.