Evidence for a regulatory role of inducible cAMP early repressor in protein kinase A-mediated enhancement of vitamin D receptor expression and modulation of …

M Huening, G Yehia, CA Molina… - Molecular …, 2002 - academic.oup.com
M Huening, G Yehia, CA Molina, S Christakos
Molecular Endocrinology, 2002academic.oup.com
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 …
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.
Oxford University Press