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Activin Modulates the Transcriptional Response of LßT2 Cells to Gonadotropin-Releasing Hormone and Alters Cellular Proliferation

Departments of Medicine (H.Z., B.L., R.T., N.J.G.W.) and Reproductive Medicine (J.S.B., D.C., M.A.L., P.L.M.) and the University of California San Diego Cancer Center (P.L.M., N.J.G.W.), University of California, San Diego, California 92093; and the Medical Research Service (N.J.G.W.), Veterans Affairs San Diego Healthcare System, San Diego, California 92161

Address all correspondence and requests for reprints to: Nicholas Webster, Ph.D., Department of Medicine 0673, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673. E-mail: nwebster{at}ucsd.edu.

Both GnRH and activin are crucial for the correct function of pituitary gonadotrope cells. GnRH regulates LH and FSH synthesis and secretion and gonadotrope proliferation, whereas activin is essential for expression of FSH. Little is known, however, about the interplay of signaling downstream of these two hormones. In this study, we undertook expression profiling to determine how activin pretreatment alters the transcriptional response of LßT2 gonadotrope cells to GnRH stimulation. Activin treatment alone altered the transcriptional profile of 303 genes including inducing that of the 17ß-hydroxysteroid dehydrogenase B1 gene that converts estrone to 17ß-estradiol, altering the sensitivity of the cells to estrone. Furthermore, activin had a dramatic effect on the response of LßT2 cells to GnRH. Hierarchical clustering of 2453 GnRH-responsive genes identified groups of genes the response of which to GnRH was either enhanced or blunted after activin treatment. Mapping of these genes to gene ontology classifications or signaling pathways highlighted significant differences in the classes of altered genes. In the presence of activin, GnRH regulates genes in pathways controlling cell energetics, cytoskeletal rearrangements, organelle organization, and mitosis in the absence of activin, but genes controlling protein processing, cell differentiation, and secretion. Therefore, we demonstrated that activin enhanced GnRH induction of p38MAPK activity, caused GnRH-dependent phosphorylation of p53, and reduced the ability of GnRH to cause G1 arrest. Thus, although activin alone changes a modest number of transcripts, activin pretreatment dramatically alters the response to GnRH from an antiproliferative response to a more differentiated, synthetic response appropriate for a secretory cell.

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