Angiotensin-II-induced expression of proto-oncogene (c- fos, jun-B and c- jun) mRNA in bovine adrenocortical fasciculata cells (BAC) is mediated by AT-1 receptors

Abstract

We have shown previously that angiotensin-II (A-II) controls proto-oncogene (c- fos, jun-B and c- jun) mRNA accumulation in bovine adrenal fasciculata cells (BAC). Since BAC contain both subtypes (AT-1 and AT-2) of the A-II receptor, we have investigated which subtype was involved in the effect of A-II on proto-oncogene mRNA by using a selective antagonist for AT-1 (DUP 753) and for AT-2 (CGP 42112A). DUP 753, but not CGP 421 12A, inhibited the stimulatory effect of A-II on proto-oncogene mRNA, with ID 3ds of 4 × 10 −7 M, 7 × 10 −7 M and 2 × 10 −6 M for c- fos, jun-B and c- jun, respectively. Neither of the two antagonists by themselves had a direct effect on proto-oncogene mRNA. As the A-II AT-1 receptors are coupled to the phospholipase C system in BAC, we have investigated whether the A-II effects on the proto-oncogenes were mediated by protein kinase C (PKC) or by Ca 2+ calmodulin. First, activation of PKC by the phorbol ester, PMA, increased the level of the three proto-oncogene mRNAs, whereas calcium ionophore had no effect. Second, staurosporine, a specific inhibitor of PKC, reduced the stimulatory action of A-II on proto-oncogene mRNA by 80–90%, whereas trifluoroperazine, an inhibitor of calmodulin, had no significant effect. These results demonstrate that the effects of A-II on proto-oncogene mRNA are mediated by AT1 receptor subtypes, mainly through activation of the PKC pathway.