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Interactions between the Prohormone Convertase 2 Promoter and the Thyroid Hormone Receptor¹

Division of Endocrinology, Department of Medicine, Cedars-Sinai Research Institute-University of California School of Medicine (Q.L.-L., S.N., T.C.F.), Los Angeles, California 90048; Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven and the Flanders Interuniversity Institute for Biotechnology (E.J.), B-3000 Leuven, Belgium; Division of Endocrinology, Department of Medicine, West Los Angeles Veterans Affairs Medical Center, and Departments of Medicine and Physiology, University of California School of Medicine (G.A.B.), Los Angeles, California 90073; and Division of Endocrinology and Metabolism, Department of Medicine, University of Maryland (J.F.W.), Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Theodore C. Friedman, M.D., Ph.D., Charles R. Drew University of Medicine and Science, Endocrinology Division, University of California, 1721 East 120th Street, Los Angeles, California 90059. E-mail: friedmant{at}hotmail.com

The majority of prohormones are cleaved at paired basic residues to generate bioactive hormones by prohormone convertases (PCs). As PC1 and PC2, two neuroendocrine-specific PCs, appear to be the key enzymes capable of processing a variety of prohormones, alterations of PC2 and/or PC1 levels will probably have a profound effect on hormonal homeostasis. We investigated the regulation of PC2 messenger RNA (mRNA) by thyroid hormone using GH₃ cells to demonstrate that T₃ negatively regulated PC2 mRNA levels in a dose- and time-dependent fashion. Functional analysis of progressive 5'-deletions of the human (h) PC2 promoter luciferase constructs in GH₃ cells demonstrated that the regulation probably occurs at the transcriptional level, and that putative negative thyroid hormone response elements were located within the region from -44 to +137 bp relative to the transcriptional start site. Transient transfections in JEG-3 cells and COS-1 cells showed that the suppressive effect of T₃ was equally mediated by the thyroid hormone receptor (TR) isoforms TR1 and TRß1. Electrophoretic mobility shift assays using purified TR1 and retinoid X receptor-ß protein as well as GH₃ nuclear extracts showed that regions from +51 to +71 bp and from +118 to +137 bp of the hPC2 promoter bind to TR1 as both a monomer and a homodimer and with TR1/retinoid X receptor-ß as a heterodimer. Finally, the in vivo regulation of pituitary PC2 mRNA by thyroid status was demonstrated in rats. These results demonstrate that T₃ negatively regulates PC2 expression at the transcriptional level and that functional negative thyroid hormone response elements exist in the hPC2 promoter. We postulate that the alterations of PC2 activity may mediate some of the pathophysiological consequences of hypo- or hyperthyroidism.

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