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J Biol Chem. 2015 Jan 9;290(2):1129-40. doi: 10.1074/jbc.M114.590943. Epub 2014 Nov 20.

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).

Author information

1
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.
2
From the Department of Molecular Signaling, University of Yamanashi, Yamanashi 409-3898, Japan and.
3
From the Department of Molecular Signaling, University of Yamanashi, Yamanashi 409-3898, Japan and yao@yamanashi.ac.jp.

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.

KEYWORDS:

Extracellular Signal-regulated Kinase (ERK); MAP Kinase Phosphatase 3 (MKP-3); Oxidative Stress; Proliferation; Senescence; p53

PMID:
25414256
PMCID:
PMC4294480
DOI:
10.1074/jbc.M114.590943
[Indexed for MEDLINE]
Free PMC Article

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