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.
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 42112A, inhibited the stimulatory effect of A-II on proto-oncogene mRNA, with ID50s of 4 x 10(-7) M, 7 x 10(-7) M and 2 x 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 Ca2+ calmodulin. First, activation of PKC by the phorbol ester, PMA, increased the level of 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.
Viard
I
I
INSERM U 307, Hôpital Debrousse, Lyon, France.
Jaillard
C
C
Ouali
R
R
Saez
J M
JM
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern; D002147:Calmodulin / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D016762:Genes, fos; D016758:Genes, jun; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D011945:Receptors, Angiotensin / Q000502:physiology*; D015383:Zona Fasciculata / Q000378:metabolism*
D002147:Calmodulin; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D011493:Protein Kinase C