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CLCA2 as a p53-inducible senescence mediator

Chizu Tanikawa1, Hidewaki Nakagawa, Yoichi Furukawa

  • 1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Neoplasia (New York, N.Y.)
|March 21, 2012
PubMed

Insights

The tumor suppressor p53 induces senescence via chloride channel accessory 2 (CLCA2). Reduced CLCA2 expression correlates with cancer, suggesting its role in preventing malignant transformation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Senescence

Background:

  • The tumor suppressor p53 is frequently mutated in cancers.
  • p53 activation inhibits malignancy by inducing cell cycle arrest, apoptosis, DNA repair, and senescence.
  • Genes mediating p53-induced senescence are not fully understood.

Purpose of the Study:

  • Identify novel genes in the p53-mediated senescence pathway.
  • Investigate the role of chloride channel accessory 2 (CLCA2) in p53-induced senescence and cancer.

Main Methods:

  • Screening of genome-wide expression profile data sets.
  • Analysis of CLCA2 expression in response to exogenous p53 and senescence.
  • Functional studies using ectopic CLCA2 expression and small interfering RNA (siRNA).

Main Results:

  • CLCA2 was identified as a p53-inducible gene associated with senescence.
  • CLCA2 expression was induced by replicative senescence and oxidative stress in a p53-dependent manner.
  • Ectopic CLCA2 induced senescence, while CLCA2 knockdown inhibited oxidative stress-induced senescence.
  • Reduced CLCA2 expression was observed in various cancers, but not in precancerous lesions.

Conclusions:

  • CLCA2 is a key mediator of p53-induced cellular senescence.
  • The p53/CLCA2 pathway acts as a barrier against malignant transformation.
  • CLCA2 downregulation may contribute to cancer development, particularly in prostate cancer.

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