title: Down-regulation of wild-type p53-induced phosphatase 1 (Wip1) plays a critical role in regulating several p53-dependent functions in premature senescent tumor cells.
abstract: Premature or drug-induced senescence is a major cellular response to chemotherapy in solid tumors. The senescent phenotype develops slowly and is associated with chronic DNA damage response. We found that expression of wild-type p53-induced phosphatase 1 (Wip1) is markedly down-regulated during persistent DNA damage and after drug release during the acquisition of the senescent phenotype in carcinoma cells. We demonstrate that down-regulation of Wip1 is required for maintenance of permanent G2 arrest. In fact, we show that forced expression of Wip1 in premature senescent tumor cells induces inappropriate re-initiation of mitosis, uncontrolled polyploid progression, and cell death by mitotic failure. Most of the effects of Wip1 may be attributed to its ability to dephosphorylate p53 at Ser(15) and to inhibit DNA damage response. However, we also uncover a regulatory pathway whereby suppression of p53 Ser(15) phosphorylation is associated with enhanced phosphorylation at Ser(46), increased p53 protein levels, and induction of Noxa expression. On the whole, our data indicate that down-regulation of Wip1 expression during premature senescence plays a pivotal role in regulating several p53-dependent aspects of the senescent phenotype.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, via S. Pansini, 5, 80131 Naples, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Crescenzi
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, "Federico II" University of Naples, via S. Pansini, 5, 80131 Naples, Italy.
authors.forename: Zelinda
authors.initials: Z
authors.lastname: Raia
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, via S. Pansini, 5, 80131 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pacifico
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, via S. Pansini, 5, 80131 Naples, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Mellone
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, via S. Pansini, 5, 80131 Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Moscato
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, "Federico II" University of Naples, via S. Pansini, 5, 80131 Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palumbo
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, "Federico II" University of Naples, via S. Pansini, 5, 80131 Naples, Italy. Electronic address: leonardi@unina.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Leonardi
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence; D004249:DNA Damage / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008938:Mitosis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D000071636:Protein Phosphatase 2C; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: Cancer; Cell Death; Cellular Senescence; DNA Damage Response; Polyploidy; Wip1; p53