title: Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms.
abstract: Thyrotropin (TSH), stimulators of guanyl nucleotide regulatory protein, (sodium fluoride and guanyl-5'-yl-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. Eleven of these patients had benign follicular adenomas and six patients had differentiated thyroid carcinomas. An 8000 X 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 P32-cAMP. Thyroid neoplasms had a greater AC response to TSH than did normal thyroid tissue removed from the same patients (p less than 0.001). The AC response to NaF and Gpp(NH)p was greater in the neoplastic thyroid tissue, although in these experiments the increase was not significant. In contrast, 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 manganese (Mn+2) (2 mM) over magnesium (Mg+2) (2 mM) (p less than 0.001), whereas TSH-stimulated (p less than 0.01) and Gpp(NH)p-stimulated AC activity (p less than 0.05) were lower in the presence of Mn+2 than Mg+2. There was an excellent correlation between basal AC activity and 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. These data suggest that 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.forename: O H
authors.initials: OH
authors.lastname: Clark
authors.forename: P L
authors.initials: PL
authors.lastname: Gerend
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000378:metabolism*; D005576:Colforsin; D000242:Cyclic AMP / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D005260:Female; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000378:metabolism; D011989:Receptors, Thyrotropin; D012969:Sodium Fluoride / Q000494:pharmacology; D013961:Thyroid Gland / Q000378:metabolism* / Q000502:physiology; D013964:Thyroid Neoplasms / Q000378:metabolism*; D013972:Thyrotropin / Q000502:physiology*
chemical_list: D004224:Diterpenes; D011956:Receptors, Cell Surface; D011989:Receptors, Thyrotropin; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D012969:Sodium Fluoride; D013972:Thyrotropin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases