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Cisplatin-DNA damage in p21WAF1/Cip1 deficient mouse keratinocytes exposed to cisplatin

Hilde E van Gijssel1, Tarek A Leil, Wendy C Weinberg

  • 1Laboratory of Cellular Carcinogenesis and Tumor Promotion, CCR, National Cancer Institute, National Institutes of Health, Building 37 Room 4032, Bethesda, MD 20892-4255, USA.

Mutagenesis
|December 13, 2006
PubMed

Insights

The p21 protein influences cisplatin DNA adduct levels. Heterozygous p21 cells showed fewer platinum-DNA adducts, suggesting p21 controls adduct formation or removal.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Toxicology

Background:

  • The TP53 pathway, involving p21(WAF1/Cip1), mediates cellular responses to DNA damage, including cell cycle arrest and apoptosis.
  • Cisplatin, a chemotherapeutic agent, induces DNA damage by forming platinum-DNA adducts, such as cis-diammineplatinum-N(7)-d[GpG] and cis-diammine-platinum-N(7)-d[ApG].

Purpose of the Study:

  • To investigate the role of p21(WAF1/Cip1) in cellular responses to cisplatin-induced DNA damage.
  • To determine how p21(WAF1/Cip1) levels affect platinum-DNA adduct formation, cell cycle arrest, and apoptosis.

Main Methods:

  • Skin keratinocytes from p21(WAF1/Cip1) wild-type, heterozygous, and null mice were cultured and exposed to cisplatin.
  • Platinum-DNA adduct levels, p21(WAF1/Cip1) mRNA expression, cell cycle distribution (S-phase), and apoptosis were measured at various time points.

Main Results:

  • Heterozygous p21(WAF1/Cip1) cells exhibited significantly lower platinum-DNA adduct levels compared to wild-type and null cells.
  • Cisplatin exposure led to decreased S-phase progression and increased apoptosis in wild-type and heterozygous cells compared to null cells, but these effects did not fully explain the reduced adducts in heterozygous cells.
  • p21(WAF1/Cip1) mRNA expression was higher in wild-type cells than heterozygous cells after cisplatin exposure.

Conclusions:

  • p21(WAF1/Cip1) plays a role in modulating platinum-DNA adduct levels in response to cisplatin.
  • The findings suggest that p21(WAF1/Cip1) influences either the formation or the removal of cisplatin-DNA adducts, independent of its known roles in cell cycle arrest and apoptosis.

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