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Induction of p38δ expression plays an essential role in oncogenic ras-induced senescence

Jinny Kwong1, Michelle Chen, Dan Lv

  • 1Department of Cell and Molecular Biology.

Molecular and Cellular Biology
|July 24, 2013
PubMed

Insights

p38δ kinase drives oncogene-induced senescence independently of p53 and p16INK4A. Oncogenic Ras activates p38δ expression via the Raf-MEK-ERK pathway, AP-1, and Ets transcription factors.

Area of Science:

  • Cellular senescence
  • Tumor suppression
  • Signal transduction

Background:

  • Oncogene-induced senescence is a critical tumor-suppressing mechanism.
  • p38 mitogen-activated protein kinase (MAPK) is involved in this process.
  • The distinct roles of p38 isoforms in senescence are not fully elucidated.

Purpose of the Study:

  • To investigate the specific role of p38δ in oncogene-induced senescence.
  • To uncover the molecular mechanisms regulating p38δ expression and activity during senescence.
  • To identify novel signaling components involved in senescence induction.

Main Methods:

  • Investigated p38δ's role in oncogene-induced senescence using cellular models.
  • Analyzed the involvement of p53, p16INK4A, and DNA damage pathways.
  • Elucidated the regulatory pathway involving oncogenic Ras, Raf-MEK-ERK, AP-1, Ets, and MKK3/6.

Main Results:

  • p38δ mediates oncogene-induced senescence via a p53- and p16INK4A-independent pathway, linked to DNA damage response.
  • Oncogenic Ras activates p38δ transcription through the Raf-MEK-ERK pathway, AP-1, and Ets transcription factors.
  • p38δ protein levels increase via transcriptional activation, and its activity is enhanced by MKK3/6.

Conclusions:

  • p38δ is a key mediator of oncogene-induced senescence through a novel mechanism.
  • The Raf-1-MEK-ERK-AP-1/Ets pathway transcriptionally upregulates p38δ during senescence.
  • AP-1 and Ets transcription factors are identified as novel regulators in the senescence-inducing pathway.

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