title: 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.
authors.affiliation: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University, Health Science Center, Beijing 100191, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Cao
authors.forename: Lixiang
authors.initials: L
authors.lastname: Xue
authors.forename: Limin
authors.initials: L
authors.lastname: Han
authors.forename: Liwei
authors.initials: L
authors.lastname: Ma
authors.forename: Tianda
authors.initials: T
authors.lastname: Chen
authors.forename: Tanjun
authors.initials: T
authors.lastname: Tong
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000737:chemistry / Q000378:metabolism*; D004171:Diploidy; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025821:Polyubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases