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Parathyroid Hormone Increases Prostaglandin G/H Synthase-2 Transcription by a Cyclic Adenosine 3',5'-Monophosphate-Mediated Pathway in Murine Osteoblastic MC3T3-E1 Cells¹

Departments of Medicine and Oral Diagnosis (S.T.), University of Connecticut Health Center, Farmington, Connecticut 06030; and the Departments of Biological Chemistry and Pharmacology, Molecular Biology Institute (H.R.H.), and Laboratory of Structural Biology and Molecular Medicine (H.R.H.), University of California School of Medicine, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Barbara E. Kream, Ph.D., Department of Medicine, MC-1850, University of Connecticut Health Center, Farmington, Connecticut 06030. E-mail: kream{at}nso1.uchc.edu

PTH increased PG synthase-2 transcription in osteoblastic MC3T3-E1 cells at 30 min, as assessed by nuclear run-on assays. To determine the signaling pathways used by PTH, the activity of a construct containing the PG synthase-2 gene between nucleotides -963 and +70 linked to a luciferase reporter was analyzed in stably transfected MC3T3-E1 cells. Agents that activate the cAMP-protein kinase A or protein kinase C pathways increased PG synthase-2 promoter activity. In contrast, the calcium ionophore ionomycin was ineffective. The protein kinase A inhibitor H89 blocked PTH stimulation of PG synthase-2 promoter activity, whereas an overnight preincubation with phorbol ester to down-regulate protein kinase C did not. PTH-(3–34), a peptide that has greatly reduced ability to activate the cAMP-protein kinase A pathway, did not increase PG synthase-2 transcription or promoter activity. PTH could induce PG synthase-2 messenger RNA accumulation and PG synthase-2 transcription in the presence of cycloheximide. In addition, PTH-stimulated PG synthase-2 transcription was maintained at a high level at 2 h in the presence of cycloheximide. We conclude that PTH rapidly increases PG synthase-2 transcription in MC3T3-E1 cells, mainly through a cAMP-protein kinase A-mediated pathway without the need for protein synthesis. In contrast, the attenuation of increased PG synthase-2 transcription by PTH requires de novo protein synthesis.

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