title: p53 protein-mediated up-regulation of MAP kinase phosphatase 3 (MKP-3) contributes to the establishment of the cellular senescent phenotype through dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2).
abstract: Growth arrest is one of the essential features of cellular senescence. At present, the precise mechanisms responsible for the establishment of the senescence-associated arrested phenotype are still incompletely understood. Given that ERK1/2 is one of the major kinases controlling cell growth and proliferation, we examined the possible implication of ERK1/2. Exposure of normal rat epithelial cells to etoposide caused cellular senescence, as manifested by enlarged cell size, a flattened cell body, reduced cell proliferation, enhanced β-galactosidase activity, and elevated p53 and p21. Senescent cells displayed a blunted response to growth factor-induced cell proliferation, which was preceded by impaired ERK1/2 activation. Further analysis revealed that senescent cells expressed a significantly higher level of mitogen-activated protein phosphatase 3 (MKP-3, a cytosolic ERK1/2-targeted phosphatase), which was suppressed by blocking the transcriptional activity of the tumor suppressor p53 with pifithrin-α. Inhibition of MKP-3 activity with a specific inhibitor or siRNA enhanced basal ERK1/2 phosphorylation and promoted cell proliferation. Apart from its role in growth arrest, impairment of ERK1/2 also contributed to the resistance of senescent cells to oxidant-elicited cell injury. These results therefore indicate that p53-mediated up-regulation of MKP-3 contributes to the establishment of the senescent cellular phenotype through dephosphorylating ERK1/2. Impairment of ERK1/2 activation could be an important mechanism by which p53 controls cellular senescence.
authors.affiliation: From the Department of Molecular Signaling, University of Yamanashi, Yamanashi 409-3898, Japan and the Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100037, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: From the Department of Molecular Signaling, University of Yamanashi, Yamanashi 409-3898, Japan and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chi
authors.affiliation: From the Department of Molecular Signaling, University of Yamanashi, Yamanashi 409-3898, Japan and.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: From the Department of Molecular Signaling, University of Yamanashi, Yamanashi 409-3898, Japan and.
authors.forename: Xiling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Department of Molecular Signaling, University of Yamanashi, Yamanashi 409-3898, Japan and yao@yamanashi.ac.jp.
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D054642:Dual Specificity Phosphatase 6 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D010766:Phosphorylation; D034741:RNA, Small Interfering; D051381:Rats; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048052:Mitogen-Activated Protein Kinase 3; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6
keywords: Extracellular Signal-regulated Kinase (ERK); MAP Kinase Phosphatase 3 (MKP-3); Oxidative Stress; Proliferation; Senescence; p53