Harvey-ras gene expression and epidermal cell proliferation in dibenzo[a,l]pyrene-treated early preneoplastic SENCAR mouse skin.
Topical application of dibenzo[a,l]pyrene (DB[a,l]P) to the dorsal skin of SENCAR mice induces codon 61 (CAA Gln to CTA Leu) 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,l]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,l]P-induced hyperplasia. DB[a,l]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,l]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,l]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.
Khan
Gausal A
GA
Eppley Institute for Research in Cancer and Allied Diseases, Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Bhattacharya
Gautam
G
Mailander
Paula C
PC
Meza
Jane L
JL
Hansen
Laura A
LA
Chakravarti
Dhrubajyoti
D
D000818:Animals; D001580:Benzopyrenes; D049109:Cell Proliferation; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D011905:Genes, ras; D051379:Mice; D018632:Mice, Inbred SENCAR; D009154:Mutation; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D001580:Benzopyrenes; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D018631:ras Proteins; C041517:dibenzo(a,l)pyrene