Adenovirus-Directed Expression of a Nonphosphorylatable Mutant of CREB (cAMP Response Element-Binding Protein) Adversely Affects the Survival, but Not the Differentiation, of Rat Granulosa Cells

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Abstract
Although usually considered to be a constitu- tively expressed protein, in the primate ovary the expression of CREB (cAMP response element- binding protein) is extinguished after ovulation, and its loss is temporally associated with the cessation of proliferation of luteal cells and the ultimate commitment of the corpus luteum to undergo regression. To determine the cellular consequences of the loss of CREB expression, we expressed a nonphosphorylatable mutant of CREB (CREB M1) in primary cultures of rat gran- ulosa cells using a replication-defective adeno- virus vector. Expression of CREB M1 did not block granulosa cell differentiation as assessed by acquisition of the ability to produce estrogen and progesterone in response to FSH or forsko- lin. However, granulosa cells expressing CREB M1, but not adenovirus-directed b-galactosidase or enhanced green fluorescent protein, exhibited a 35% reduction in viability that was further re- duced to 65% after stimulation with 10 mM fors- kolin. These results demonstrate that the trophic effects of cAMP (proliferation and survival) on ovarian granulosa cells are functionally separate from the effects of cAMP on differentiation and provide novel evidence that CREB may function as a cell survival factor in the ovary. The sepa- ration of signaling pathways that govern differ- entiation and survival in the ovary thereby pro- vides a mechanism by which progesterone production, which is absolutely essential for the maintenance of pregnancy, can continue despite the cessation of proliferation of luteal cells and their commitment to cell death (luteolysis). (Mo- lecular Endocrinology 13: 1364-1372, 1999)

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