Journal Article

Genetic alterations in N-bis(2-hydroxypropyl)nitrosamine-induced rat transplantable thyroid carcinoma lines: analysis of the TSH-R, G(alpha)s, ras and p53 genes.

Y Kitahori, H Naitoh, N Konishi, T Ohnishi and Y Hiasa

in Carcinogenesis

Volume 18, issue 2, pages 265-269
Published in print February 1997 | ISSN: 0143-3334
Published online February 1997 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/18.2.265
Genetic alterations in N-bis(2-hydroxypropyl)nitrosamine-induced rat transplantable thyroid carcinoma lines: analysis of the TSH-R, G(alpha)s, ras and p53 genes.

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It has recently been shown that point mutations of the TSH-R or G(alpha)s genes are associated with autonomous hyperfunctioning thyroid adenomas and differentiated carcinomas. We therefore screened for mutations in the TSH-R, G(alpha)s, ras and p53 genes in nine rat transplantable thyroid carcinoma lines derived from tumors induced by DHPN as a chemical carcinogen. Mutations were identified using single-strand conformation polymorphism and DNA sequencing analysis. Point mutations in G(alpha)s codon 201 (CGC-->CAC) were detected in three lines (33%), resulting in a heterozygous alteration (Arg-->His) in the expressed G(alpha)s protein. The mean intracellular cAMP level (2.30 +/- 0.27 nmol/mg) of the three mutated cell lines was significantly increased as compared with that of the lines (1.54 +/- 0.32 nmol/mg) without the G(alpha)s mutation (P < 0.01, by paired t-test). Also, these three cell lines had an activating mutation in Ki-ras codon 12 (GGT-->GAT). One TSH-R gene mutation was found with a base substitution in codon 636 (TGC-->TGT) but no amino acid change. No p53 gene (exons 5-8) mutations were detected in any of the cell lines analyzed. The results suggest that mutational activation of the G(alpha)s gene may play a tumorigenic role through constitutive activation of the cAMP pathway and that G-->A point mutations in the G(alpha)s and ras genes in thyroid carcinomas directly reflect interaction of the chemical carcinogen with guanine residues in DNA.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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