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MECHANISMS OF INTERACTIONS OF FSH AND IGF-I ON GRANULOSA CELL PROLIFERATION AND DIFFERENTIATION.
Cunningham, Melissa1, Hammond, James1, 1
ABSTRACT- The growth and differentiation of ovarian follicles is regulated by follicle stimulating hormone (FSH), in conjunction with insulin-like growth factor-I (IGF-I) which appears to function as a local amplifier of FSH. In vivo, FSH stimulates proliferation of granulosa cells; however, there are few mechanistic studies of this FSH effect in vitro. We have used serum-free cultures of porcine granulosa cells to study the actions of IGF-I and FSH on granulosa cell proliferation and differentiation, and to examine the cytoplasmic kinase pathways that mediate this interrelationship. FSH, IGF-I, and their combination stimulated replicative activity as monitored by PCNA, Ki67, and cell counts. In addition, they enhanced cellular differentiation as indicated by increased production of progesterone and expression of the steroidogenic acute regulatory protein (StAR) at the mRNA and protein levels. Inhibition of the dominant kinase pathways with H89, PD98059, and LY294002 under our culture conditions indicated that phosphatidylinositol 3-kinase (PI3-K) is the major effector of hormone-induced growth. Additionally, inhibition of PI3-K dramatically induced progesterone secretion. Blockade of the mitogen-activated protein kinase (MAPK) pathway had a similar but less dramatic effect on the same endpoints. This system should enable us to elucidate the points of overlap, if any, between the several kinase pathways. They likely have synergistic actions on cell growth. However, our data also suggest antagonism between the growth- and differentiation-promoting effects mediated by the PI3-K pathway.
KEY WORDS: FSH, IGF, PI3-K, granulosa cell, signal transduction, StAR
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