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Submitted on October 4, 2001
Accepted on May 20, 2002
1 Dept. of Biochemistry and Molecular Biology and Department of Obstetrics and Gynecology, University of Medicine and Dentistry of New Jersey --New Jersey Medical School and Graduate School of Biomedical Sciences, Newark, NJ 07103 Key Words: Inducible Cyclic Adenosine 3', 5'-Monophosphate Early Repressor (ICER), vitamin D receptor, 24-hydroxylase, osteopontin, transcription, protein kinase A (PKA), cAMP, PTH
* To whom correspondence should be addressed. E-mail: christak{at}umdnj.edu.
PTH (PTH) or activators of protein kinase A (PKA) up-regulate the vitamin D receptor (VDR) and augment the induction by 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) of the expression of target genes [24-hydroxylase (24OHase) and osteopontin (OPN)] 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-
coding sequence, cAMP or PTH enhancement of 1,25-(OH)2D3-induced OPN and 24OHase mRNA and transcription is inhibited. The vitamin D response element (VDRE) 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 CRE-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.
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