Regulation of parathyroid hormone gene expression and peptide secretion in human parathyroid cells.
In cell cultures prepared from human parathyroid adenomas, parathyroid hormone (PTH) mRNA expression decreased slowly. During short-term incubations (less than 24 h), a low calcium concentration (0.5 mmol/l) and protein kinase C activator TPA (12-O-tetradecanoyl phorbol 13-acetate) (160 nmol/l) increased PTH secretion (60%; p < 0.05), while a high extracellular calcium concentration (2.5 mmol/l) reduced PTH secretion (60%; p < 0.05). The TPA could block the inhibitory effect of a high calcium level on PTH peptide secretion. All these agents had no effect on PTH mRNA accumulation in short-term experiments. In long-term cultures (more than 24 h), a low calcium level increased and a high calcium level reduced both PTH mRNA (85 and 34%; p < 0.05) and peptide secretion (140 and 80%; p < 0.05), respectively. The TPA reduced PTH mRNA accumulation down to 30% (p < 0.05) and PTH secretion down to 14% (p < 0.05) in a time- and dose-dependent fashion. The TPA also reversed the stimulatory effect of hypocalcemia on PTH mRNA accumulation and peptide secretion. Protein kinase C inhibitors staurosporine (100 nmol/l) and H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride) (50 mumol/l) had similar effects to TPA on PTH gene expression and peptide secretion in long-term cultures. The results support the hypothesis that extracellular calcium regulates PTH mRNA accumulation and PTH secretion via protein kinase C.
Liu
J
J
Department of Pathology, University of Helsinki, Finland.
Kahri
A
A
Teppo
A M
AM
Voutilainen
R
R
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000236:Adenoma / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000470:Alkaloids / Q000494:pharmacology; D001483:Base Sequence; D015152:Blotting, Northern; D002118:Calcium / Q000494:pharmacology; D002455:Cell Division; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006961:Hyperparathyroidism / Q000209:etiology; D007546:Isoquinolines / Q000494:pharmacology; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000737:chemistry; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D010282:Parathyroid Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D007546:Isoquinolines; D015345:Oligonucleotide Probes; D010281:Parathyroid Hormone; D010879:Piperazines; D012333:RNA, Messenger; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003513:Cycloheximide; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium