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Implication of p53-dependent cellular senescence related gene, TARSH in tumor suppression

Takeshi Wakoh1, Natsuko Uekawa, Kunihiko Terauchi

  • 1Department of Mechanism of Aging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3, Gengo, Morioka-Cho, Obu-City, Aichi 474-8522, Japan.

Biochemical and Biophysical Research Communications
|April 3, 2009
PubMed

Insights

A novel gene, TARSH, was found to inhibit mouse embryonic fibroblast proliferation and increase senescence. Its suppression is linked to p53-dependent growth arrest and multicentrosome formation, suggesting a role in lung cancer development.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Cellular senescence is a key process in aging and tumor suppression.
  • The gene TARSH (target of NESH-SH3) is implicated in replicative senescence.
  • TARSH expression is reduced in clinical lung cancer specimens, but its role in tumorigenesis is unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism of TARSH regulation in pulmonary tumorigenesis.
  • To investigate the functional role of TARSH in cellular senescence and proliferation.
  • To determine the relationship between TARSH and p53-dependent pathways.

Main Methods:

  • Short hairpin RNA (shRNA) was used to reduce TARSH gene expression in mouse embryonic fibroblasts (MEFs).
  • Senescence-associated beta-galactosidase (SA-beta-gal) activity was measured to assess senescence.
  • Experiments were conducted using p53-/- MEFs to evaluate p53 dependency.
  • Multicentrosome formation was analyzed in TARSH-deficient MEFs.

Main Results:

  • Reduction of TARSH gene expression inhibited MEF proliferation and increased SA-beta-gal activity.
  • Loss of TARSH led to p53-dependent p21(Cip1) accumulation, causing growth arrest.
  • TARSH reduction induced multicentrosome formation, associated with chromosome instability.
  • These findings link TARSH to replicative senescence and tumor development.

Conclusions:

  • TARSH plays a critical role in the proliferation of replicative senescence.
  • TARSH acts as a potential trigger for tumor development by influencing cell cycle control and genomic stability.
  • Targeting TARSH may offer a novel therapeutic strategy for lung cancer.

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