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Submitted on December 20, 2004
Accepted on September 6, 2005
Department of Cell Biology and Biochemistry (P.R.M., S.P.C., Y.J., D.M.S.), Texas Tech University Health Sciences Center, Lubbock, Texas 79430; Scott Department of Urology (S.R.K.), Baylor College of Medicine, Houston, TX 77030; Physiologie et Physiopathologie (R.C.), Université Pierre et Marie Curie, UMR CNRS 7079, Paris, France; Institute of Reproductive and Developmental Biology (I.T.H.), Imperial College London, London W12 0NN, U. K.
* To whom correspondence should be addressed. E-mail: doug.stocco{at}ttmc.ttuhsc.edu.
Growth factors are known to play diverse roles in steroidogenesis, a process regulated by the mitochondrial steroidogenic acute regulatory (StAR) protein. The mechanism of action of one such growth factor, insulin-like growth factor-I (IGF-I), was investigated in mouse Leydig tumor (mLTC-1) cells to determine its potential role in the regulation of StAR expression. MLTC-1 cells treated with IGF-I demonstrated temporal and concentration dependent increases in StAR expression and steroid synthesis. However, IGF-I had no effect on cytochrome P450 side-chain cleavage or 3
-hydroxysteroid dehydrogenase protein levels. IGF-I was capable of augmenting (Bu)2cAMP-stimulated steroidogenic responsiveness in these cells. The steroidogenic potential of IGF-I was also confirmed in primary cultures of isolated mouse Leydig cells. IGF-I increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), an event inhibited by the MAPK/ERK inhibitors, PD098059 and U0126. Interestingly, inhibition of ERK activity enhanced IGF-I mediated StAR protein expression but phosphorylation of StAR was undetectable, an observation in contrast to that seen with (Bu)2cAMP signaling. Further studies demonstrated that these events were tightly correlated with the expression of DAX-1 and scavenger receptor class B type 1 (SR-B1). While both PKA and PKC signaling were involved in the IGF-I mediated steroidogenic response, the majority of the effects of IGF-I were found to be mediated by the PKC pathway. Transcriptional activation of the StAR gene by IGF-I was influenced by several transcription factors, its up-regulation being dependent on phosphorylation of the cAMP response element-binding protein (CREB) and the AP-1 family member, c-Jun. Conversely, StAR gene transcription was markedly inhibited by expression of non-phosphorylatable CREB (Ser133Ala), dominant negative A-CREB, and dominant negative c-Jun (TAM-67) mutants. Collectively, the present studies identify molecular events in IGF-I signaling that may influence testicular growth, development and the Leydig cell steroidogenic machinery through autocrine/paracrine regulation.
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