Regulation of growth by ACTH in the Y-1 line of mouse adrenocortical cells.

Y-1 adrenal cells were cell cycle arrested by serum starvation to characterize a G0-->G1-->S transition in these cells. Cycle arrested Y-1 cells start to enter S phase 8h after serum feeding, reaching more than 90% cells synthesizing DNA by 24h. ACTH displays a dual effect in the G0-->G1-->S transition: 2h ACTH treatment stimulates DNA synthesis initiation, but longer treatments inhibit S phase entry. This dual effect of ACTH is similar to the antagonistic actions of PMA (phorbol-12-miristate-13-acetate) on the G0-->G1-->S transition. However ACTH and PMA are likely to have different mechanisms of action. ACTH inhibitory effect requires PKA, whereas PMA inhibitory effect is not dependent on PKA. ACTH induces the proto-oncogenes c-fos and c-jun, but inhibits the expression of the c-myc proto-oncogene. PMA, on the other hand, induces equally well c-fos, c-jun and c-myc. We hypothesize that ACTH promotes G0-->G1 transition by induction of c-fos and c-jun and blocks G1-->S transition by c-myc inhibition.