論文

査読有り 国際誌
2015年1月9日

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).

The Journal of biological chemistry
  • Hui Zhang
  • ,
  • Yuan Chi
  • ,
  • Kun Gao
  • ,
  • Xiling Zhang
  • ,
  • Jian Yao

290
2
開始ページ
1129
終了ページ
40
記述言語
英語
掲載種別
DOI
10.1074/jbc.M114.590943

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.

リンク情報
DOI
https://doi.org/10.1074/jbc.M114.590943
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/25414256
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294480
ID情報
  • DOI : 10.1074/jbc.M114.590943
  • PubMed ID : 25414256
  • PubMed Central 記事ID : PMC4294480

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