HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Zirngibl, R. A Articles by Aubin, J. E Search for Related Content PubMed PubMed Citation Articles by Zirngibl, R. A Articles by Aubin, J. E

Department of Molecular Genetics, Faculty of Medicine, University of Toronto, 1 Kings College Circle, Medical Sciences Building Room 6230, Toronto, <br>Ontario M5S 1A8, Canada

(Correspondence should be addressed to J E Aubin; Email: jane.aubin{at}utoronto.ca)

The authors have nothing to disclose.

We previously demonstrated that the orphan nuclear receptor, estrogen receptor-related receptor (ERR) is highly expressed in osteoblasts and osteoclasts, regulates osteogenesis and expression of osteoblast-associated markers in the rat calvaria cell differentiation system, and is dysregulated in the rat ovariectomy model of postmenopausal osteoporosis. There are conflicting published data on the transcriptional regulation by ERR of the gene for osteopontin (OPN), an extracellular matrix protein required in bone remodeling, and a potential direct target mediating ERR effects in bone. We therefore readdressed OPN gene regulation by ERR in both osteoblastic (rat osteosarcoma ROS17/2.8 cells) and non-osteoblastic (HeLa) cell lines using a mouse proximal 2 kb OPN promoter fragment. A minimal OPN promoter fragment spanning from –56 to +9 bp is activated in HeLa cells but repressed it in ROS17/2.8 cells. Adenine scanning mutagenesis revealed the presence of a non-canonical ERR response element in this minimal promoter. Surprisingly, prototypical inactivating mutations in the activation function 2 (AF2) domain or a naturally occurring allelic variant of ERR (ERRH408) were all better activators than wild-type ERR in HeLa cells, activities that were generally paralleled by repression in ROS17/2.8 cells. Finally, we found that the N-terminus of ERR harbors a repressor domain that acts in a cell context-dependent manner. We conclude that OPN is an ERR target gene whose promoter is regulated by ERR in a cell context-dependent manner and that a predicted silencing mutation in AF2 or a more flexible helix 12 increases ERR transcriptional activity, effects with implications for ERR as a therapeutic target in bone.

This article has been cited by other articles:

				B.-C. Jeong, Y.-S. Lee, Y.-Y. Park, I.-H. Bae, D.-K. Kim, S.-H. Koo, H.-R. Choi, S.-H. Kim, R. T. Franceschi, J.-T. Koh, et al. The Orphan Nuclear Receptor Estrogen Receptor-related Receptor {gamma} Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation J. Biol. Chem., May 22, 2009; 284(21): 14211 - 14218. [Abstract] [Full Text] [PDF]

				L. H. El Touny and P. P. Banerjee Identification of a Biphasic Role for Genistein in the Regulation of Prostate Cancer Growth and Metastasis Cancer Res., April 15, 2009; 69(8): 3695 - 3703. [Abstract] [Full Text] [PDF]

				L. Lam Shang Leen, C. Filipe, A. Billon, B. Garmy-Susini, S. Jalvy, F. Robbesyn, D. Daret, C. Allieres, S. R. Rittling, N. Werner, et al. Estrogen-Stimulated Endothelial Repair Requires Osteopontin Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2131 - 2136. [Abstract] [Full Text] [PDF]