Evidence for a regulatory role of inducible cAMP early repressor in protein kinase a-mediated enhancement of vitamin D receptor expression and modulation of hormone action.
Parathyroid hormone (PTH) or activators of protein kinase A (PKA) up-regulate the vitamin D receptor (VDR) and augment the induction by 1,25-dihydroxyvitamin D(3) of the expression of target genes (24-hydroxylase and osteopontin) in osteoblastic cells. To understand regulatory mechanisms involved, we asked whether the inducible cAMP early repressor (ICER), which serves as a dominant negative regulator of cAMP-induced transcription in other endocrine systems, may similarly play a role in modulation of vitamin D hormone action. In this study we demonstrate that PTH or 8-bromo-cAMP rapidly induces ICER mRNA and protein in osteoblastic cells. In UMR 106 osteoblastic cells transfected with an expression vector containing the ICER II-gamma coding sequence, cAMP or PTH enhancement of 1,25-dihydroxyvitamin D(3)-induced osteopontin and 24-hydroxylase mRNA and transcription is inhibited. The vitamin D response element is sufficient for the PKA enhancement of VDR-mediated transcription and is also sufficient to observe the inhibitory effect of ICER. Our data indicate that the mechanism of the inhibitory effect of ICER involves an inhibition of PKA-induced VDR transcription, and this inhibition may be mediated in part by binding of ICER to a cAMP response element-like sequence in the VDR promoter. This study provides evidence for the first time that ICER has a key regulatory role in the PKA enhancement of VDR transcription and therefore in the cross-talk between the PKA signaling pathway and the vitamin D endocrine system.
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School and Graduate School of Biomedical Sciences, Newark, New Jersey 07103, USA.
Michael
M
Huening
Ghassan
G
Yehia
Carlos A
CA
Molina
Sylvia
S
Christakos
D000818:Animals; D015153:Blotting, Western; D002112:Calcifediol / Q000494:pharmacology; D045744:Cell Line, Tumor; D053493:Cholestanetriol 26-Monooxygenase; D000242:Cyclic AMP / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D010281:Parathyroid Hormone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012097:Repressor Proteins; D013250:Steroid Hydroxylases / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D002112:Calcifediol