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

Michael Huening, Ghassan Yehia, Carlos Molina, Sylvia Christakos

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31 Citations (Scopus)

Abstract

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 D3 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-γ coding sequence, cAMP or PTH enhancement of 1,25-dihydroxyvitamin D3-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.

Original languageEnglish
Pages (from-to)2052-2064
Number of pages13
JournalMolecular Endocrinology
Volume16
Issue number9
DOIs
StatePublished - 1 Sep 2002

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Repressor Proteins
Calcitriol Receptors
Cyclic AMP-Dependent Protein Kinases
Hormones
Parathyroid Hormone
Osteopontin
Endocrine System
Calcitriol
Mixed Function Oxygenases
Vitamin D
Vitamin D Response Element
8-Bromo Cyclic Adenosine Monophosphate
Messenger RNA
Response Elements
Up-Regulation
Gene Expression

Cite this

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abstract = "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 D3 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-γ coding sequence, cAMP or PTH enhancement of 1,25-dihydroxyvitamin D3-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.",
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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. / Huening, Michael; Yehia, Ghassan; Molina, Carlos; Christakos, Sylvia.

In: Molecular Endocrinology, Vol. 16, No. 9, 01.09.2002, p. 2052-2064.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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AU - Huening, Michael

AU - Yehia, Ghassan

AU - Molina, Carlos

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