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p38α and p38γ mediate oncogenic ras-induced senescence through differential mechanisms

Academic Article
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Overview

related to degree

  • Kwong, Jinny, Ph.D. in Biology, Scripps Research 2005 - 2013

authors

  • Kwong, Jinny
  • Hong, L. X.
  • Liao, R.
  • Deng, Q. D.
  • Han, Jiahuai
  • Sun, Peiqing

publication date

  • April 2009

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Oncogene-induced senescence is a tumor-suppressive defense mechanism triggered upon activation of certain oncogenes in normal cells. Recently, the senescence response to oncogene activation has been shown to act as a bona fide barrier to cancer development in vivo. Multiple previous studies have implicated the importance of the p38 MAPK pathway in oncogene-induced senescence. However, the contribution of each of the four p38 isoforms (encoded by different genes) to senescence induction is unclear. In the current study, we demonstrated that p38alpha and p38gamma, but not p38beta, play an essential role in oncogenic ras-induced senescence. Both p38alpha and p38gamma are expressed in primary human fibroblasts and are activated upon transduction of oncogenic ras. Small hairpin RNA-mediated silencing of p38alpha or p38gamma expression abrogated ras-induced senescence, whereas constitutive activation of p38alpha and p38gamma caused premature senescence. Furthermore, upon activation by oncogenic ras, p38gamma stimulated the transcriptional activity of p53 by phosphorylating p53 at Ser(33), suggesting that the ability of p38gamma to mediate senescence is at least partly achieved through p53. However, p38alpha contributed to ras-inducted senescence via a p53-indepdendent mechanism in cells by mediating ras-induced expression of p16(INK4A), another key senescence effector. These findings have identified p38alpha and p38gamma as essential components of the signaling pathway that regulates the tumor-suppressing senescence response, providing insights into the molecular mechanisms underlying the differential involvement of the p38 isoforms in senescence induction.

subject areas

  • Cell Aging
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation
  • Mitogen-Activated Protein Kinase 12
  • Mitogen-Activated Protein Kinase 14
  • Models, Biological
  • Phosphorylation
  • Protein Isoforms
  • Serine
  • Signal Transduction
  • Transcription, Genetic
  • Tumor Suppressor Protein p53
  • ras Proteins
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Identity

PubMed Central ID

  • PMC2670128

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M808327200

PubMed ID

  • 19251701
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Additional Document Info

start page

  • 11237

end page

  • 11246

volume

  • 284

issue

  • 17

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