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Published on: September 27, 2016

p27 suppresses arsenite-induced Hsp27/Hsp70 expression through inhibiting JNK2/c-Jun- and HSF-1-dependent pathways

Jinyi Liu1, Dongyun Zhang, Xiaoyi Mi

  • 1Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.

The Journal of Biological Chemistry
|June 23, 2010
PubMed

Insights

The tumor suppressor p27 negatively regulates heat shock proteins Hsp27 and Hsp70 expression. This regulation occurs via the JNK2/c-Jun and HSF-1 pathways, revealing new anticancer mechanisms for p27.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Oncology

Background:

  • p27 is an atypical tumor suppressor involved in cell cycle regulation.
  • Emerging evidence suggests p27 has broader tumor-suppressive roles beyond cell cycle control.
  • The precise molecular mechanisms of p27's diverse anticancer functions remain largely undefined.

Purpose of the Study:

  • To investigate the molecular mechanisms by which p27 exerts its tumor-suppressive functions.
  • To determine the role of p27 in regulating the expression of heat shock proteins (HSPs) upon stress.
  • To elucidate the signaling pathways involved in p27-mediated regulation of HSPs.

Main Methods:

  • Gene knockout (p27(-/-)) and knockdown (p27 shRNA) were used to deplete p27 expression.
  • Quantitative PCR and Western blotting were employed to assess mRNA and protein levels of Hsp27 and Hsp70.
  • Arsenite exposure was used as a cellular stressor.
  • Involvement of signaling pathways (JNK1/2, c-Jun, HSF-1) was investigated through functional interference.

Main Results:

  • Depletion of p27 led to significant upregulation of Hsp27 and Hsp70 expression at both transcriptional and protein levels following arsenite exposure.
  • Arsenite-induced activation of JNK2/c-Jun and HSF-1 pathways was markedly increased in p27-deficient cells.
  • Inhibition of JNK2, c-Jun, or HSF-1, but not JNK1, abrogated the arsenite-induced expression of Hsp27 and Hsp70 in p27-depleted cells.

Conclusions:

  • p27 suppresses the expression of Hsp27 and Hsp70 at the transcriptional level.
  • This suppression is mediated through the JNK2/c-Jun and HSF-1 signaling pathways.
  • These findings reveal novel molecular mechanisms contributing to the tumor-suppressive activity of p27.

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