ACTIVIN-INDUCED INHIBIN ALPHA-SUBUNIT PRODUCTION BY RAT GRANULOSA-CELLS REQUIRES ENDOGENOUS INSULIN-LIKE-GROWTH-FACTOR

Inhibin-alpha subunit (lnh-alpha) gene expression is important for gra nulosa cell (GC) differentiation and prevention of ovarian tumorigenes is, Studies on Inh-alpha regulation have implicated activin and insuli n-like growth factor-I (IGF-I) in the mechanisms of expression, Here w e present evidence that endogenously produced IGF-I plays an obligator y role in activin-induced Inh-alpha production, Primary cultures of ra t GC were incubated with increasing concentrations of various regulato ry molecules, and the levels of Inh-alpha protein and its mRNA were me asured in conditioned medium and cells, respectively, Recombinant acti vin A stimulated Inh-alpha expression, and the effects were dose-and t ime-dependent, The receptor tyrosine kinase inhibitor tyrphostin A23 c aused a dose-dependent inhibition of activin-dependent Inh-alpha expre ssion, whereas the inactive isomer, A63, had no effect, The stimulator y effect of activin was also blocked in a dose-dependent manner by add ed IGF binding protein-4 or -5, and the effects were reversed by IGF-I . Moreover; increasing concentrations of an anti-IGF-l antibody had a similar inhibitory effect on activin-stimulated Inh-alpha expression, Collectively, these results suggest, for the first time, that endogeno usly produced IGF-I is required for activin stimulation of Inh-alpha e xpression in cultured rat GC.