title: Low incidence of point mutations detected in the p53 tumor suppressor gene from chemically induced rat renal mesenchymal tumors.
abstract: Previous studies have shown renal mesenchymal tumors (RMTs) induced in rats by a single intrarenal injection of nickel subsulfide and iron are more pleomorphic and metastatically aggressive than RMTs induced by a single ip injection of methyl(methoxymethyl)nitrosamine (DMN-OMe). While both RMT types contain high levels of K-ras activation, the specific mutational spectra within codon 12 of K-ras are quite different. Nickel subsulfide and iron-induced tumors exhibited codon 12 GGT-->GTT transversions exclusively, while DMN-OMe RMTs showed a wide array of codon 12 mutations, as well as mutations within codons 61 and 63 [K. G. Higinbotham, J. M. Rice, B. A. Diwan, K. S. Kasprzak, C. D. Reed, and A. O. Perantoni, Cancer Res., 52: 4747-4751, 1992; K. G. Higinbotham, J. M. Rice, and A. O. Perantoni, Mol. Carcinog., 5: 136-139, 1992]. In an effort to further correlate carcinogen-specific molecular events in renal tumors, we investigated the p53 tumor suppressor gene in RMTs induced by these two carcinogens for the presence of point mutations. The evolutionarily conserved portion of the coding region of the gene, including part of exon 4 through exon 10, was surveyed for point mutations utilizing single-strand conformation polymorphism and chemical cleavage of mismatches analyses. None (0 of 10) of the nickel subsulfide and iron-induced RMTs and only 1 of 10 DMN-OMe-induced tumors that were evaluated contained point mutations within this portion of the p53 gene. Direct sequencing of the one single-strand conformation polymorphism and chemical cleavage of mismatches-"positive" DMN-OMe-induced RMT revealed a GCC-->GTC (Ala-->Val) transition in codon 345 within exon 10. These results suggest that the different tumorigenic phenotypes exhibited by these two RMTs are not the result of specific mutations or patterns of mutations within the portion of the p53 gene examined and that the mutated p53 tumorigenic pathway, whereby p53 plays a major role in many human neoplasms, does not function in RMTs induced by either agent.
authors.affiliation: Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702.
authors.forename: C M
authors.initials: CM
authors.lastname: Weghorst
authors.forename: K H
authors.initials: KH
authors.lastname: Dragnev
authors.forename: G S
authors.initials: GS
authors.lastname: Buzard
authors.forename: K L
authors.initials: KL
authors.lastname: Thorne
authors.forename: G F
authors.initials: GF
authors.lastname: Vandeborne
authors.forename: K A
authors.initials: KA
authors.lastname: Vincent
authors.forename: J M
authors.initials: JM
authors.lastname: Rice
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics*; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009532:Nickel; D017354:Point Mutation; D051381:Rats; D011916:Rats, Inbred F344; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; C029938:nickel sulfate; C014659:methyl(acetoxymethyl)nitrosamine; D009532:Nickel; D004128:Dimethylnitrosamine