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Transcript Profiling of Immediate Early Genes Reveals a Unique Role for Activating Transcription Factor 3 in Mediating Activation of the Glycoprotein Hormone -Subunit Promoter by Gonadotropin-Releasing Hormone

Department of Biomedical Sciences (J.X., S.P.B., M.S.R.), Cornell University, Ithaca, New York 14853; Department of Biomedical Sciences (T.M.N.), Colorado State University, Fort Collins, Colorado 80523; and Department of Neurology (B.J.E., S.C.S.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Mark S. Roberson Ph.D., Associate Professor of Physiology, T3-004d Veterinary Research Tower, Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853. E-mail: msr14{at}cornell.edu.

Recent studies profiling immediate early gene responses to GnRH in the LßT2 gonadotrope cell model revealed increased expression of numerous genes including activating transcription factor (ATF) 3. The present studies demonstrate similar results with GnRH administration in vivo in ovariectomized mice. In this model, ATF3 mRNA was markedly up-regulated at 20, 40, and 60 min after in vivo administration of a GnRH analog. In T3-1 gonadotrope cells, ATF3 mRNA and protein were induced by GnRH in a manner consistent with in vivo observations. Pharmacological studies implicated a combined role for the activities of protein kinase C isozymes, ERK and c-Jun N-terminal kinase, in modulating ATF3 expression. The role of ATF3 was further investigated in the activation of the human glycoprotein hormone -subunit gene promoter. GnRH induced the -subunit promoter-luciferase reporter approximately 16-fold, and this induction was completely abolished with mutations in the dual cAMP response elements (CREs) or the combined inhibition of GnRH-induced ERK and c-Jun N-terminal kinase. GnRH induced recruitment of ATF3, c-Jun, and c-Fos to the dual CREs. Overexpression and specific knockdown of ATF3 by small inhibitory RNA implicate a functional role for ATF3 in mediating activation of the -subunit gene promoter. These studies provide clear evidence that ATF3 is a key immediate early gene induced by GnRH administration in vivo and in the T3-1 gonadotrope cell model. These studies support the conclusion that the dual CREs of the human -subunit promoter are the target of GnRH-induced MAPK regulation through ATF3.

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