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Role of Transforming Growth Factor (TGF)-ß Type I and TGF-ß Type II Receptors in the TGF-ß1-Regulated Gene Expression in Pituitary Prolactin-Secreting Lactotropes¹

Department of Veterinary and Comparative Anatomy (D.K.S., M.P., A.D., M.B.G.), Pharmacology and Physiology, Center for Reproductive Biology (D.K.S.), Washington State University, Pullman, Washington 99164-6520; and Department of Cell Biology (M.E., H.M.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6838

Address all correspondence and requests for reprints to: Dr. Dipak K. Sarkar, Professor, Department of VCAPP, Washington State University, Pullman, Washington 99164-6520. E-mail: sarkar{at}vetmed.wsu.edu

Transforming growth factor ß1 (TGF-ß1) inhibits pituitary lactotrope proliferation and secretion of PRL in an autocrine/paracrine manner. In this study, the role of TGF-ß1 type I (TßR-I) and TGF-ß type II (TßR-II) receptors in TGF-ß1-regulated gene expression in lactotropes was determined using anterior pituitary cells known to be responsive to TGF-ß1 growth inhibition and using a transformed PR1 cell line known to be nonresponsive to TGF-ß1 growth inhibition. Treatment with TGF-ß1 inhibited cell proliferation and decreased PRL mRNA levels in anterior pituitary cells, but in PR-1 cells, the treatment caused only decreased PRL mRNA levels. Affinity labeling of TGF-ß binding proteins indicated that anterior pituitary cells contain several TGF-ß-binding protein complexes, including the 65 kDa size TßR-I and 95 kDa size TßR-II. In the PR1 cells, the major complex found was similar to the 65 kDa size of TßR-I. Immunocytochemistry identified TßR-I and TßR-II receptor proteins in lactotropes but detected primarily TßR-I receptor protein in PR1 cells. RT-PCR detection of TßR-I and TßR-II mRNA identified both receptor mRNA transcripts in anterior pituitary cells and in PR1 cells but the levels of TßR-II and TßR-I mRNA transcripts in PR1 cells was much lower than that in anterior pituitary cells. Determination of the TGF-ß1 gene responses in PR1 cells following TßR-I and TßR-II gene transfection indicated that PR1 cells transactivate transcription of the TGF-ß-responsive p3TP-Lux reporter in the absence of cotransfected TßR-II receptor. The introduction of the TßR-II receptor alone or in combination with TßR-I confer ligand-independent reporter transactivation in these cells. When only TßR-I was introduced along with reporter, a ligand-dependent transactivation was observed. These data suggest for the first time that the TGF-ß1-mediated transcriptional activation response can be distinguished from the growth response in lactotropes. Furthermore, the TGF-ß1 gene-transcription response is less dependent on TßR-II receptor expression than is the TGF-ß1 growth-inhibitory response.

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