Carcinogenesis, Vol 18, 265-269, Copyright © 1997 by Oxford University Press
Y Kitahori, H Naitoh, N Konishi, T Ohnishi and Y Hiasa
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.
ARTICLES
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
Second Department of Pathology, Nara Medical University, Shijo-cho, Kashihara, Japan.
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