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Regulation of Granulosa Cell-Derived Insulin-Like Growth Factor Binding Proteins (IGFBPs): Role for Protein Kinase-C in the Pre- and Posttranslational Modulation of IGFBP-4 and IGFBP-5¹

^a 95 Bulldog Blvd., Suite 204, Melbourne, Florida 32901 ^b Department of Obstetrics and Gynecology, Sungkyunkwan University, School of Medicine, Samsung Medical Center, Seoul, Korea ^c Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Huntsman Cancer Institute, Salt Lake City, Utah 84112 ^d Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, Maryland 21201 ^e Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Beer Sheva, Israel ^f Department of Pediatrics, University of Oregon Health Sciences Center, Portland, Oregon 97201

A growing body of information suggests antigonadotropic and atretogenic roles for granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs) 4 and 5 during ovarian folliculogenesis. Activation of protein kinase-A (PKA) in rat granulosa cells has been shown to modulate the relative expression of IGFBP-4 and -5 transcripts and proteins. In this article, we assess the role of protein kinase-C (PKC) in this regard. Provision of granulosa cells with phorbol 12-myristate 13-acetate (PMA) (but not 4PMA, an inert analogue), a tumor-promoting phorbol ester and an established activator of PKC, was without significant effect on the expression of IGFBP-4 transcripts but resulted in biphasic dose-dependent alterations in IGFBP-5 transcripts and in the accumulation of the IGFBP-4 and -5 proteins. Comparable effects were noted for GnRH, an established PKC agonist. Provision of staurosporine, a potent inhibitor of the catalytic subunit of PKC, produced significant dose-dependent decrements in the relative expression of IGFBP-5 transcripts. Treatment with FSH (presumptively PKA-mediated) markedly attenuated the ability of PMA or GnRH to upregulate the accumulation of the IGFBP-5 (but not IGFBP-4) protein. Taken together, our present findings indicate that the modulation of rat ovarian IGFBP-4 and -5 is PKC as well as PKA dependent and that these two signaling pathways interact in a diametrically opposed and antagonistic fashion.

First decision: 28 November 2001.

¹ This research was supported in part by NIH Research grant HD 30288 (E.Y.A.), CAPES/Brazil BEX 1007/99-8 (A.B.T.), and CNPq/Brazil 870.313/97-5 (A.B.T.).

² Correspondence: Eli Y. Adashi, Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Huntsman Cancer Institute, 2000 Circle of Hope, Room 5221, Salt Lake City, UT 84112. FAX: 801 585 9256; eadashi{at}hsc.utah.edu

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