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Prostaglandin F2 Stimulates the Expression and Secretion of Transforming Growth Factor B1 Via Induction of the Early Growth Response 1 Gene (EGR1) in the Bovine Corpus Luteum

Department of Veterans Affairs Medical Center (X.H., E.W.A., J.S.D.), Omaha, Nebraska 68105; Olson Center for Women’s Health (X.H., E.W.A., C.J., J.S.D.), Department of Obstetrics and Gynecology, Department of Physiology and Biophysics (S.K.R.), and Departments of Biochemistry and Molecular Biology, and Pharmacology and Experimental Neurosciences (J.S.D.), University of Nebraska Medical Center, Omaha, Nebraska 68198-3255; Department of Reproductive Medicine (D.-b.C.), University of California-San Diego Medical Center, La Jolla, California 92093; Department of Animal Sciences (J.L.P.), Ohio State University, Wooster, Ohio 44691; Department of Biomedical Sciences (T.R.H.), Colorado State University, Fort Collins, Colorado 80523; and Vincent Center for Reproductive Biology (B.R.R.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696

Address all correspondence and requests for reprints to: John S. Davis, Ph.D., 983255 Nebraska Medical Center, Omaha, Nebraska 68198-3255. E-mail: jsdavis{at}unmc.edu.

In most mammals, prostaglandin F2 (PGF2) is believed to be a trigger that induces the regression of the corpus luteum (CL), whereby progesterone synthesis is inhibited, the luteal structure involutes, and the reproductive cycle resumes. Studies have shown that the early growth response 1 (EGR1) protein can induce the expression of proapoptotic proteins, suggesting that EGR1 may play a role in luteal regression. Our hypothesis is that EGR1 mediates the actions of PGF2 by inducing the expression of TGF β1 (TGFB1), a key tissue remodeling protein. The levels of EGR1 mRNA and protein were up-regulated in the bovine CL during PGF2-induced luteolysis in vivo and in PGF2-treated luteal cells in vitro. Using chemical and genetic approaches, the RAF/MAPK kinase (MEK) 1/ERK pathway was identified as a proximal signaling event required for the induction of EGR1 in PGF2-treated cells. Treatment with PGF2 increased the expression of TGFB1 mRNA and protein as well as the binding of EGR1 protein to TGFB1 promoter in bovine luteal cells. The effect of PGF2 on TGFB1 expression was mimicked by a protein kinase C (PKC)/RAF/MEK1/ERK activator or adenoviral-mediated expression of EGR1. The stimulatory effect of PGF2 on TGFB1 mRNA and TGFB1 protein secretion was inhibited by blockade of MEK1/ERK signaling and by adenoviral-mediated expression of NAB2, an EGR1 binding protein that inhibits EGR1 transcriptional activity. Treatment of luteal cells with TGFB1 reduced progesterone secretion, implicating TGFB1 in luteal regression. These studies demonstrate that PGF2 stimulates the expression of EGR1 and TGFB1 in the CL. We suggest that EGR1 plays a role in the expression of genes whose cognate proteins coordinate luteal regression.