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

Abstract

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 4alphaPMA, 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.

Up date on IGFBP-4: regulation of IGFBP-4 levels and functions, in vitro and in vivo

“…Similarly, in vitro, IGFBP-4 mRNA expression by bovine ovarian thecal cells is enhanced by LH [50]. Rat granulosa cell-derived IGFBP-4 mRNA expression displays relatively limited regulation in response to treatment with FSH, IGF-I or activation of the proteinase kinase C signaling [51,52].…”

Functional significance of the signal transduction pathways Akt and Erk in ovarian follicles: in vitro and in vivo studies in cattle and sheep

“…It has been established that IGF stimulates proliferation of granulosa and theca cells, and enhances the ability of gonadotropins to stimulate steroidogenesis in both granulosa and theca cells [ 16 - 18 ]. In addition, it has been shown that IGF has a direct anti-apoptotic effect and is selectively expressed in healthy follicles compared with small atretic follicles [ 19 ]. The Akt and Erk pathways are considered the principle signalling pathways that mediate the effects of IGF [ 20 ].…”

Follicle-Stimulating Hormone and Estradiol Interact to Stimulate Glutathione Synthesis in Rat Ovarian Follicles and Granulosa Cells1

“…PKI at a concentration of 1 lM was shown to inhibit PKA activity by 80% and to completely abolish PKA activity at 100 lM in pancreatic b cells, whereas it has no effect on PKC at concentrations up to 10 lM [51]. At the 50-lM concentration used in the present study, it is possible that some inhibition of PKC also occurred, and PKC signaling is important in granulosa cells [52]. Therefore, the divergent effects of H89 and PKI on GCLC protein observed in the present studies may have been due to inhibition of other signaling kinase pathways by either of these inhibitors.…”