Harvey-ras gene expression and epidermal cell proliferation in dibenzo[a,I]pyrene-treated early preneoplastic SENCAR mouse skin

Gausal A. Khan, Gautam Bhattacharya, Paula C. Mailander, Jane L. Meza, Laura A. Hansen, Dhrubajyoti Chakravarti

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Topical application of dibenzo[a,I]pyrene (DB[a,I]P) to the dorsal skin of SENCAR mice induces codon 61 (CAAGln to CTALeu) mutations in the Harvey (H)-ras gene within 12 h after treatment. Between days 1 and 3, the frequency of these mutations increases rapidly, suggesting that skin cells carrying the codon 61 mutations proliferate in this period. We have investigated DB[a,I]P-treated mouse skin (12 h-7 d) for further evidence of H-ras expression and epidermal cell proliferation. Two waves of cell proliferation were observed: the first wave (1-2 d) correlated with the clonal proliferation of codon 61-mutated cells, and the second wave (3-7 d) correlated with DB[a,I]P-induced hyperplasia. DB[a,I]P-induced early preneoplastic cell proliferation correlated with H-ras and specific G1 cyclin expression. Total H-ras protein and cyclin D1 were found to increase during DB[a,I]P-induced hyperplasia, but the levels of guanosine triphosphate-bound (active) H-ras protein and cyclin E were increased during the putative clonal proliferation of codon 61-mutated cells. These results suggest that DB[a,I]P-induced oncogenically mutated cells proliferate in early preneoplastic skin. As this proliferation occurs in the absence of any promoting treatment, we propose that this phenomenon is a tumor initiation event.

Original languageEnglish (US)
Pages (from-to)567-574
Number of pages8
JournalJournal of Investigative Dermatology
Issue number3
StatePublished - Sep 1 2005


All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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