INSULIN-LIKE GROWTH FACTOR-II IN HUMAN FETAL ADRENALS - REGULATION BYACTH, PROTEIN-KINASE-C AND GROWTH-FACTORS

Insulin-like growth factor-II (IGF-II) may be one of the most importan t local growth factors in human fetal adrenals (HFAs), where its mRNA levels are upregulated by ACTH. We have investigated whether protein k inase C (PKC)-dependent mechanisms and various polypeptide growth fact ors participate in the regulation of IGF-II gene expression in culture d HFA cells, and whether HFA cells secrete IGF-II peptide into the cul ture medium. ACTH enhanced IGF-II mRNA accumulation dose- and time-dep endently, maximally four- to sixfold, and this increase was inhibited dose-dependently (0.01-100 mug/l) by 12-O-tetradecanoyl phorbol-13-ace tate (TPA), a PKC activator. TPA decreased basal IGF-II mRNA levels by approximately 55%. Staurosporine, a PKC inhibitor, abolished the inhi bitory effects of TPA and induced accumulation of IGF-II mRNA. Dibutyr yl cyclic AMP, cholera toxin and forskolin increased IGF-II mRNA accum ulation as much as ACTH, and TPA inhibited these stimulations in a sim ilar way. ACTH increased the IGF-II peptide concentration in most expe riments, but this increase was modest in comparison with IGF-II mRNA c hanges. TPA. although it decreased IGF-II mRNA levels, tended to incre ase 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. Tran sforming growth factor-beta1 inhibited IGF-II mRNA accumulation to the same extent as TPA. Epidermal growth factor and basic fibroblast grow th factor did not change IGF-II mRNA levels. Our results confirm previ ous reports that ACTH is an important regulator of IGF-II in human fet al adrenals, and show that IGF-II gene expression is under multifactor ial control, which includes the PKC system and polypeptide growth fact ors.