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Modulation of Estrogen Production and 17ß-Hydroxysteroid Dehydrogenase-Type 1, Cytochrome P450 Aromatase, c-Met, and Protein Kinase B Messenger Ribonucleic Acid Content in Rat Ovarian Granulosa Cells by Hepatocyte Growth Factor and Follicle-Stimulating Hormone¹

^a Southern Illinois University (SIU) School of Dental Medicine, Department of Applied Dental Medicine, Alton, Illinois 62002-4700

ABSTRACT

Hepatocyte growth factor (HGF) suppresses FSH-dependent estradiol-17ß (E₂) production in ovarian granulosa cells (GC). The mechanisms of action for HGF in GC are unknown; however, activation of the HGF receptor, c-Met, can induce c-Akt/protein kinase B (PKB)-mediated signal transduction in nonovarian cells. Using immature rat GC, the present study investigated the effects of HGF within the estrogen biosynthetic pathway, concomitant with changes in c-Met and PKB mRNA expression. Granulosa cells were incubated with androstenedione and FSH, HGF, and/or dibutyryl-cAMP (Bu₂-cAMP). Follicle-stimulating hormone and Bu₂-cAMP each stimulated estrone (E₁) and E₂ synthesis at 48 h. Hepatocyte growth factor suppressed FSH-dependent E₂, but not E₁, synthesis. Semiquantitative reverse transcription–polymerase chain reaction showed that HGF impaired FSH-supported 17ß-hydroxysteroid dehydrogenase type-1 (17ß-HSD) and cytochrome P450 aromatase (P450arom) mRNA levels. Hepatocyte growth factor did not reduce E₂ synthesis or 17ß-HSD and P450arom mRNA expression in the presence of Bu₂-cAMP at 48 h. The FSH and HGF each down-modulated c-Met mRNA accumulation, whereas Bu₂-cAMP increased c-Met mRNA content. Between 0 and 48 h a biphasic change in PKB mRNA content occurred with either FSH or HGF; however, PKB mRNA accumulation was augmented by HGF. Collectively, results suggest that HGF can suppress E₂ production in GC by disrupting cAMP-dependent 17ß-HSD and P450arom. Changes in c-Met and PKB mRNA content provide a potential link between HGF signaling and the FSH-dependent mechanisms that control the steroidogenic differentiation of GC.

FOOTNOTES

First decision: 30 November 1999.

¹ This work was funded by an SIU-Edwardsville Graduate School Research Grant (R.J.Z.) and an SIU-SDM Dean's Student Fellowship DSRF99-3 (B.E.R.).

² Correspondence: Rob Zachow, SIU School of Dental Medicine, 2800 College Ave., Alton, IL 62002-4700. FAX: 618 474 7150; rzachow{at}siue.edu

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