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Department of Medicine (M.A.C., Q.Z., J.M.H.), The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033; and University of Illinois at Chicago and Chicago Veterans Healthcare System (T.G.U.), Chicago, Illinois 60612
Address all correspondence and requests for reprints to: James M. Hammond, The Pennsylvania State University Hershey Medical Center, 500 University Drive, C6636, Hershey, Pennsylvania 17033. E-mail: jhammond{at}psu.edu
The forkhead family of transcription factors is conserved in evolution and known to play critical roles in the regulation of cellular differentiation and proliferation in many systems. The current studies demonstrate for the first time that forkhead homolog in rhabdomyosarcoma (FKHR) (FoxO1a) is expressed in porcine granulosa cells, and FSH stimulates FKHR phosphorylation and regulates its subcellular localization in this system. RT-PCR and Western blot studies demonstrated that FKHR is expressed and showed no change in FKHR message or protein levels in response to FSH (0–6 h). However, [32p]-orthophosphate labeling of cultured granulosa cells revealed robust phosphorylation after FSH treatment for 30 min. In addition, FSH caused nuclear exclusion of FKHR in these cells, apparently through the phosphatidylinositol 3-kinase signal transduction pathway. The cytosolic accumulation of FKHR protein that was observed in FSH-treated cells both by Western blot and immunohistochemistry was blocked when the cells were preincubated with the phosphatidylinositol 3-kinase inhibitor LY294002. Our data also demonstrate that Akt/protein kinase B, an established kinase for FKHR, is phosphorylated in response to FSH treatment. Interestingly, although FKHR was phosphorylated by 30 min after FSH treatment, the time course for Akt phosphorylation was relatively delayed and sustained. Although these studies do not preclude Akt involvement in FSH-stimulated FKHR phosphorylation, they do suggest that other kinases may contribute to rapid signaling to FKHR. Because FKHR has been shown to activate genes involved in apoptosis and growth inhibition, FSH may promote growth and survival by initiating the phosphorylation of FKHR, causing its nuclear exclusion, and reducing its effect as a cell cycle arrest or death-promoting transcription factor.
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