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p12(CDK2-AP1) mediates DNA damage responses induced by cisplatin

Yong Kim1, Jim McBride, Rong Zhang

  • 1School of Dentistry and Dental Research Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.

Oncogene
|November 16, 2004
PubMed

Insights

p12(CDK2-AP1) deficiency enhances DNA repair and confers resistance to cisplatin chemotherapy. This suggests p12(CDK2-AP1) modulation could improve oral cancer treatment outcomes.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Cisplatin is a cornerstone chemotherapy agent for various cancers, including oral and head and neck cancers.
  • Understanding cellular mechanisms of cisplatin resistance is crucial for improving treatment efficacy.
  • The role of p12(CDK2-AP1) in cellular responses to DNA-damaging agents like cisplatin remains largely unexplored.

Purpose of the Study:

  • To investigate the biological function of p12(CDK2-AP1) in cellular responses to cisplatin treatment.
  • To determine if p12(CDK2-AP1) influences DNA repair, apoptosis, and cell cycle progression following cisplatin exposure.
  • To evaluate the therapeutic potential of targeting p12(CDK2-AP1) in oral/head and neck cancers.

Main Methods:

  • Generation of murine ES p12(CDK2-AP1) knockout clones via targeted gene disruption.
  • Assessment of cellular proliferation, cell cycle distribution (S and G2/M phases), DNA repair activity (host cell reactivation assay), and apoptosis.
  • Validation using stable p12(CDK2-AP1) short interfering RNA (siRNA) clones in human oral keratinocytes and measurement of CDK2 kinase activity.

Main Results:

  • p12(CDK2-AP1) knockout clones exhibited increased proliferation, elevated S-phase, and reduced G2/M populations.
  • These knockout clones demonstrated resistance to cisplatin, enhanced DNA repair, and significantly reduced apoptosis.
  • Downregulation of p12(CDK2-AP1) in human cells confirmed cisplatin resistance, and sustained CDK2 kinase activity was observed in knockout cells post-cisplatin treatment.

Conclusions:

  • p12(CDK2-AP1) plays a significant role in mediating cellular responses to cisplatin, primarily by modulating CDK2 kinase activity.
  • Loss of p12(CDK2-AP1) confers resistance to cisplatin through enhanced DNA repair and reduced apoptosis.
  • p12(CDK2-AP1) represents a potential gene therapeutic target for oral/head and neck cancers when combined with DNA-damaging agents like cisplatin.

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