The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms.
The development and progression of thyroid tumors are associated with phenotype-specific mutations of genes involved in growth control. Thyroid cell growth is controlled in part by the interaction of TSH with its receptor, with subsequent activation of the GTP-binding protein and its effector, adenylyl cyclase. The resulting increase in intracellular cAMP stimulates growth in thyrocytes. The TSH receptor (TSH-R) is a seven-transmembrane domain receptor. Intracellular domains of the TSH-R important for signal transduction and which may serve as targets for mutational activation have been defined. In addition, mutations at specific loci of the alpha-subunit of G-protein in human thyroid tumors have been described. We examined 92 benign and malignant neoplastic thyroid tissues for possible mutations of the intracytoplasmic domains of the TSH-R known to be involved in signal transduction and for mutations within the hot spots of Gs alpha. Screening was carried out by single strand conformation polymorphism (TSH-R) or denaturing gradient gel electrophoresis (Gs alpha) of polymerase chain reaction-amplified tumor DNA. No mutations were observed in the cytoplasmic domains of the TSH-R, except for a neutral base substitution in codon 460 (GCG [Ala]-->GCA [Ala]) in 3 tumors, which was also present in constitutional DNA from the affected individuals. A heterozygous mutation of codon 201 of Gs alpha (GGT [Arg]-CAT [His]) was observed in a nodule from an adenomatous goiter. In addition, a codon 227 mutation (CAG [Glu]-CAT [His]) was identified in a follicular adenoma. We conclude that mutational activation of the intracytoplasmatic domains of the TSH-R is not a significant mechanism of thyroid tumorigenesis, whereas putative activating mutations within exons 8 and 9 of Gs alpha occur infrequently in some benign follicular tumors.
Division of Endocrinology, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles 90048.
K
K
Matsuo
E
E
Friedman
P V
PV
Gejman
J A
JA
Fagin
D001483:Base Sequence; D004273:DNA, Neoplasm / Q000235:genetics; D004586:Electrophoresis; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D009857:Oncogenes; D011110:Polymorphism, Genetic; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm; D015345:Oligonucleotide Probes; D011989:Receptors, Thyrotropin; D019204:GTP-Binding Proteins