Tyrphostins inhibit follicle-stimulating hormone-mediated functions in cultured rat ovarian granulosa cells

Seri Gomberg-Malool, Rei Ziv, Yael Re'em, Israel Posner, Alexander Levitzki, Joseph Orly*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

FSH induces the expression of cholesterol side-chain cleavage cytochrome P450 (P450scc) in rat ovarian granulosa cells. The present study reveals that the tyrphostin AG18, a member of novel protein tyrosine kinase inhibitors, can arrest the FSH-induced synthesis of P450scc with an apparent IC50 of 30 μM. Total inhibition of P450scc expression was achieved at 80 μM AG18. AG18-mediated inhibition of P450scc was also observed when the enzyme was induced by prostaglandin E2, forskolin, or 8-bromo-cAMP. Studies examining functional LH receptors showed that the tyrphostin inhibits the expression of FSH-induced LH receptors. The drug did not affect FSH-induced cAMP accumulation, suggesting that it may interfere with the flow of FSH signal transduction at a site distal to intracellular accumulation of cAMP. Control experiments demonstrated that the inhibitory action of AG18 was reversible, did not hamper total protein synthesis in the cells, and did not change the adenine nucleotide (ATP:ADP:AMP) ratio or their levels in the treated cells. A cell-free assay of cAMP-dependent protein kinase showed that the tyrphostin AG18 does not affect this enzyme activity up to concentrations above 200 μM. These results suggest that a putative tyrosine kinase activity is involved in the gonadotropin signal transduction pathway leading to expression of functional genes in ovarian cells.

Original languageEnglish
Pages (from-to)362-370
Number of pages9
JournalEndocrinology
Volume132
Issue number1
StatePublished - Jan 1993

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