Abstract |
The potent mitogen and tumor promoter, phorbol 12-myristate 13-acetate (PMA), has a primary action via activation of calcium-dependent protein kinase C. The treatment of monolayer cultures of human fetal adrenal neocortex (HFA) cells with PMA (50-250 nM) stimulated basal dehydroepiandrosterone sulfate (DS) secretion 2-3 fold. ACTH-treated HFA cells secreted amounts of DS and cortisol (F) 10-50 fold greater than basal secretions. PMA (250 nM) addition with ACTH to HFA cells decreased DS and F secretions at least 75% on days 2 and 3 of treatment. Treatment of HFA cells with 4 alpha-phorbol, which does not activate calcium-dependent protein kinase C, did not inhibit steroidogenesis. The attenuated rates of steroidogenesis after PMA treatment correlated with the decreased amounts of steroid 11 beta, 17 alpha- and 21-hydroxylase cholesterol side-chain cleavage steroid dehydrogenase and sulfotransferase activities. The decrease of steroid 17 alpha-hydroxylase activity correlated with the decreased amount of cytochrome P-450(17) alpha as determined after protein immunoblotting of NaDodSO4 cell lysates. After PMA treatment the ACTH-promoted increases of hydroxysteroid sulfotransferase and dehydrogenase activities of HFA cells were suppressed. PMA (50 nM) inhibited cAMP accumulation in ACTH-treated HFA cells, while 4 alpha-phorbol had no effect. Importantly, dibutyryl cAMP (0.2 mM) treatment of HFA cells did not reverse phorbol ester-promoted attenuation of steroidogenesis. We conclude that, in the presence of ACTH, phorbol ester chronically inhibits both cAMP synthesis and cAMP-dependent protein kinase action with resultant decreased steroidogenic enzyme synthesis and steroid production. This may be a consequence of activation, migration and a slow degradation of protein kinase C activity. These multifaceted actions of phorbol ester and associated protein kinase C activation may have critical effects on the ontogeny of fetal adrenal function.
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Authors | J I Mason, B R Carr, W E Rainey |
Journal | Endocrine research
(Endocr Res)
Vol. 12
Issue 4
Pg. 447-67
( 1986)
ISSN: 0743-5800 [Print] England |
PMID | 3030721
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Diglycerides
- Phorbol Esters
- Phorbols
- Dehydroepiandrosterone
- Dehydroepiandrosterone Sulfate
- Bucladesine
- Adrenocorticotropic Hormone
- Cyclic AMP
- Steroid Hydroxylases
- Protein Kinase C
- Tetradecanoylphorbol Acetate
- Hydrocortisone
- phorbol
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Topics |
- Adrenal Cortex
(embryology)
- Adrenocorticotropic Hormone
(pharmacology)
- Bucladesine
(pharmacology)
- Cells, Cultured
- Cyclic AMP
(metabolism)
- Dehydroepiandrosterone
(analogs & derivatives, metabolism)
- Dehydroepiandrosterone Sulfate
- Diglycerides
(metabolism)
- Humans
- Hydrocortisone
(metabolism)
- Phorbol Esters
(pharmacology)
- Phorbols
(pharmacology)
- Protein Kinase C
(metabolism)
- Steroid Hydroxylases
(metabolism)
- Tetradecanoylphorbol Acetate
(pharmacology)
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