Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms
Clark, O.H.; Gerend, P.L.
Surgery 97(5): 539-546
1985
ISSN/ISBN: 0039-6060 PMID: 2986305 Document Number: 246426
Thyrotropin (TSH) stimulators of guanyl nucleotide regulatory protein (NaF and guanyl-yl-5'-imido-diphosphate [Gpp(NH)p]) and a stimulator of the catalytic unit of adenylate cyclase (AC) (forskolin) were used to probe the TSH receptor-guanyl nucleotide regulatory protein-cyclase unit in normal and neoplastic thyroid tissue from 17 patients. Of these patients, 11 had benign follicular adenomas and 6 patients had differentiated thyroid carcinomas. An 8000 .times. g particulate fraction that is rich in thyroid plasma membranes was prepared and the activity of AC was determined by the conversion of .alpha.-32P-ATP to 32P-cAMP. Thyroid neoplasms had a greater AC response to TSH than did normal thyroid tissue removed from the same patients (P < 0.001). The AC response to NaF and Gpp(NH)p was greater in the neoplastic thyroid tissue although the increase was not significant. The AC response to forskolin was comparable in normal (573 .+-. 129) and neoplastic (526 .+-. 132) thyroid tissue (mean .+-. SEM). The effects of NaF, Gpp(NH)p and forskolin on AC activity were additive with TSH when used at concentrations for optimal AC activity. Low concentrations of NaF and Gpp(NH)p stimulated AC activity whereas high concentrations of NaF and Gpp(NH)p assayed either together or separately inhibited AC activity. When forskolin and NaF were assayed together there was a greater than additive effect or potentiated effect on activity. Basal AC activity was increased in the presence of Mn2+ (2 mM) over Mg2+ (2 mM) (P < 0.001), whereas TSH-stimulated (P < 0.01) and Gpp(NH)p-stimulated AC activity (P < 0.05) were lower in the presence of Mn2+ than Mg2+. There was an excellent correlation between basal AC activity in response to forskolin in both normal and neoplastic thyroid tissue, whereas there was no correlation between basal AC activity and TSH-stimulated AC activity in the thyroid neoplasms. The abnormality responsible for the greater AC response to TSH in neoplastic thyroid tissue is proximal to the catalytic unit of AC and most probably is due to an alteration in the guanyl nucleotide regulatory protein or in the coupling of the guanyl nucleotide regulatory protein to either the receptor or the catalytic unit of AC. The correlation of basal AC activity and forskolin-stimulated AC activity, yet lack of correlation of basal AC activity and TSH-stimulated AC activity in the thyroid neoplasms, suggests that at least 2 factors regulate AC activity and presumably thyroid tumor function and/or growth. One of these factors in TSH dependent, the other TSH independent.