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A functional and quantitative mutational analysis of p53 mutations in yeast indicates strand biases and different roles of mutations in DMBA- and BBN-induced tumors in rats.

Abstract：

:In order to analyze the mutational events and to understand the biological significance of the p53 gene in chemical carcinogenesis, we applied a new yeast-based p53 functional assay to ovarian tumors induced by 7, 12-dimethylbenz[a]anthracene (DMBA), as well as to transitional cell carcinomas of the urinary bladder induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in rats. The assay demonstrated that 15 of 19 DMBA induced tumors harbored clonal p53 mutations, which is consistent with the expectations of the "clonal expansion" hypothesis. The majority of the mutations were purine (AG) to pyrimidine (CT) transversions (12/19) on the non-transcribed (sense) strand (NTS), which is likely to be due to depurination created by DMBA adduct formation on the NTS. In contrast, we found no pyrimidine to purine [corrected] transversion on the NTS. After cessation of BBN treatment, BBN-induced multifocal lesions in the bladder contained heterogeneous p53 mutations at an early stage. In the later stage, however, clonal p53 mutations were identified in 4 out of 7 bladders analyzed, conforming with the concept of "field cancerization". The observed base substitutions were G-->A (1/6) or C -->T transitions (2/6), and mutations at T (3/6) on the NTS in clonal mutations, together with non-clonal mutations, showing a preference of C-->T to G-->A (17 vs. 0). Thus, preferential repair was found in the transcribed strand of the p53 gene, whether modified by DMBA or by BBN carcinogens. Very similar mutation patterns were observed between clonal and non-clonal mutations in the DMBA- and BBN-induced tumors, indicating that the rat yeast p53 functional assay can be a potential tool for the characterization of in vivo mutation patterns of p53, when modified by chemical carcinogens.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Yamamoto K,Nakata D,Tada M,Tonoki H,Nishida T,Hirai A,Ba Y,Aoyama T,Hamada J,Furuuchi K,Harada H,Hirai K,Shibahara N,Katsuoka Y,Moriuchi T

doi

10.1002/(sici)1097-0215(19991126)83:5<700::aid-ijc

keywords:

subject

Has Abstract

pub_date

1999-11-26 00:00:00

pages

700-5

issue

eissn

0020-7136

issn

1097-0215

pii

10.1002/(SICI)1097-0215(19991126)83:5<700::AID-IJC

journal_volume

pub_type

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A functional and quantitative mutational analysis of p53 mutations in yeast indicates strand biases and different roles of mutations in DMBA- and BBN-induced tumors in rats.