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Gene. 2014 Apr 10;539(1):50-7. doi: 10.1016/j.gene.2014.01.063. Epub 2014 Feb 2.

Unliganded estrogen receptor α stimulates bone sialoprotein gene expression.

Author information

1
Department of Periodontology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan; Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan.
2
Department of Periodontology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan.
3
Department of Periodontology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan; Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan. Electronic address: ogata.yorimasa@nihon-u.ac.jp.

Abstract

Estrogen is one of the steroid hormones essential for skeletal development. The estrogen receptor (ER) is a transcription factor and a member of the steroid receptor superfamily. There are two different forms of the ER, usually referred to as α and β, each encoded by a separate gene. Hormone-activated ERs form dimers, since the two forms are coexpressed in many cell types. Bone sialoprotein (BSP) is a tissue-specific acidic glycoprotein that is expressed by differentiated osteoblasts, odontoblasts and cementoblasts during the initial formation of mineralized tissue. To determine the molecular basis of the tissue-specific expression of BSP and its regulation by estrogen and the ER, we have analyzed the effects of β-estradiol and ERα on BSP gene transcription. ERα protein levels were increased after ERα overexpression in ROS17/2.8 cells. While BSP mRNA levels were increased by ERα overexpression, the endogenous and overexpressed BSP mRNA levels were not changed by β-estradiol (10(-8)M, 24 h). Luciferase activities of different sized BSP promoter constructs (pLUC3~6) were increased by ERα overexpression, whereas basal and induced luciferase activities by ERα overexpression were not influenced by β-estradiol. Effects of ERα overexpression were abrogated by 2 bp mutations in either the cAMP response element (CRE) or activator protein 1 (AP1)/glucocorticoid response element (GRE). Gel shift analyses showed that ERα overexpression increased binding to the CRE and AP1/GRE elements. Notably, the CRE-protein complexes were disrupted by ERα, CREB and phospho-CREB antibodies. The AP1/GRE-protein complexes were supershifted by the c-Fos antibody. These studies demonstrate that ERα stimulates BSP gene transcription in a ligand-independent manner by targeting the CRE and AP1/GRE elements in the rat BSP gene promoter.

KEYWORDS:

Activator protein 1; Bone sialoprotein; Estrogen; Estrogen receptor; Osteoblasts; Transcription; cAMP response element

PMID:
24495337
DOI:
10.1016/j.gene.2014.01.063
[Indexed for MEDLINE]
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