Insulin-like growth factor-II in human fetal adrenals: regulation by ACTH, protein kinase C and growth factors.
Insulin-like growth factor-II (IGF-II) may be one of the most important local growth factors in human fetal adrenals (HFAs), where its mRNA levels are upregulated by ACTH. We have investigated whether protein kinase C (PKC)-dependent mechanisms and various polypeptide growth factors participate in the regulation of IGF-II gene expression in cultured HFA cells, and whether HFA cells secrete IGF-II peptide into the culture medium. ACTH enhanced IGF-II mRNA accumulation dose- and time-dependently, maximally four- to sixfold, and this increase was inhibited dose-dependently (0.01-100 micrograms/l) by 12-O-tetradecanoyl phorbol-13-acetate (TPA), a PKC activator. TPA decreased basal IGF-II mRNA levels by approximately 55%. Staurosporine, a PKC inhibitor, abolished the inhibitory effects of TPA and induced accumulation of IGF-II mRNA. Dibutyryl cyclic AMP, cholera toxin and forskolin increased IGF-II mRNA accumulation as much as ACTH, and TPA inhibited these stimulations in a similar way. ACTH increased the IGF-II peptide concentration in most experiments, but this increase was modest in comparison with IGF-II mRNA changes. TPA, although it decreased IGF-II mRNA levels, tended to increase IGF-II peptide in the medium. Additions of GH, IGF-I and IGF-II to the cell culture medium also increased IGF-II mRNA accumulation. Transforming growth factor-beta 1 inhibited IGF-II mRNA accumulation to the same extent as TPA. Epidermal growth factor and basic fibroblast growth factor did not change IGF-II mRNA levels. Our results confirm previous reports that ACTH is an important regulator of IGF-II in human fetal adrenals, and show that IGF-II gene expression is under multifactorial control, which includes the PKC system and polypeptide growth factors.
Department of Pathology, University of Helsinki, Finland.
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V
Ilvesmäki
W F
WF
Blum
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R
Voutilainen
D000311:Adrenal Glands / Q000166:cytology / Q000196:embryology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology / Q000502:physiology*; D000470:Alkaloids / Q000494:pharmacology; D015152:Blotting, Northern; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology*; D005796:Genes / Q000235:genetics*; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000470:Alkaloids; D006133:Growth Substances; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D005576:Colforsin; D003994:Bucladesine; D007335:Insulin-Like Growth Factor II; D000324:Adrenocorticotropic Hormone; D002772:Cholera Toxin; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate