UNMASKING A GROWTH-PROMOTING EFFECT OF THE ADRENOCORTICOTROPIC HORMONE IN Y1 MOUSE ADRENOCORTICAL TUMOR-CELLS

The adrenocorticotropic hormone (ACTH) inhibits the growth of Y1 mouse adrenocortical tumor cells as well as normal adrenocortical cells in culture but stimulates adrenocortical cell growth in vivo. In this stu dy, we investigated this paradoxical effect of ACTH on cell proliferat ion in Y1 adrenal cells and have unmasked a growth promoting effect of the hormone. Y1 cells were arrested in the G(1) phase of the cell cyc le by serum starvation and monitored for progression through S phase b y measuring [H-3]thymidine incorporation into DNA and by measuring the number of nuclei labeled with bromodeoxyuridine. Y1 cells were stimul ated to progress through S phase and to divide after a brief pulse of ACTH (up to 2 h), This effect of ACTH appeared to be cAMP independent, since ACTH also induced cell cycle progression in Kin-8, a Y1 mutant with defective cAMP-dependent protein kinase activity, The growth-prom oting effect of ACTH in Y1 was preceded by the rapid activation of p44 and p42 mitogen-activated protein kinases and by the accumulation of c-FOS protein, In contrast, continuous treatment with ACTH (14 h) inhi bited cell cycle progression in Y1 cells by a cAMP-dependent pathway. The inhibitory effect of ACTH mapped to the midpoint of G,, Together, the results demonstrate a dual effect of ACTH on cell cycle progress, a cAMP-independent growth-promoting effect early in G(1) possibly medi ated by mitogen-activated protein kinase and c-FOS, and a cAMP-depende nt inhibitory effect at mid-G(1). It is suggested that the growth-inhi bitory effect of ACTH at mid-G(1) represents an ACTH-regulated check p oint that limits cell cycle progression.