Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

Vanacker, Jean‐Marc; Bonnelye, Edith; Delmarre, Cateline; Laudet, Vincent

doi:10.1038/sj.onc.1202167

Cited by 89 publications

(100 citation statements)

References 24 publications

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“…5). Recently, the osteopontin gene promoter, stimulated by ERR␣ as well as estrogen-bound ER␣ through SFRE, was found (41). These studies have broadened the spectrum of genes potentially regulated by ER␣.…”

Section: Discussionmentioning

confidence: 99%

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Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Zhang

Teng

2000

Journal of Biological Chemistry

130

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The human estrogen receptor-related receptor (ERR␣1, NR3B1a) was shown to bind a steroidogenic factor binding element (SFRE), TCAAGGTCATC, 26 base pairs upstream from the estrogen response element (ERE) of the human lactoferrin gene promoter. A mutation made at SFRE significantly reduced estrogen-dependent transcription from the lactoferrin ERE in human endometrial cells. In this study, we demonstrated that ERR␣1 binds both SFRE and ERE elements and constitutively transactivates the lactoferrin gene promoter. In DNase I footprinting protection analysis, both SFRE and ERE regions were protected by glutathione S-transferase-ERR␣1 fusion protein. The receptor formed two protein-DNA complexes with either SFRE or ERE in electrophoresis mobility shift assay. Homodimerization of ERR␣1 was confirmed with the mammalian two-hybrid system. ERR␣1 activates reporter constructs containing various types of estrogen response elements in endometrial and non-endometrial cells in transient transfection experiments. Overexpressing the coactivator, SRC1a or GRIP1, further enhances ERR␣1-induced transcriptional activity. We demonstrated that the AF2 domain of ERR␣1 is essential for the transactivation function and that deletion or mutation at this region abrogates the activation capability. Protein-protein interaction between the SRC1a and ERR␣1 C terminus was confirmed with a GST glutathione S-transferase "pull-down" assay. When comparing ERR␣1 and the estrogen receptor ␣ (ER␣) in many of the experiments, we found that ER␣ can also bind SFRE of the lactoferrin gene and transactivate the promoter activity in a ligand-dependent manner. The present study demonstrated that ERR␣1 binds similar DNA elements as ER␣ and confers its transactivation function constitutively. Therefore, ERR␣1 may actively modulate the estrogen response of lactoferrin gene as well as other estrogen-responsive genes.

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Section: Discussionmentioning

confidence: 99%

“…Recently, a diverse class of genes that possesses ERR␣1 binding element was identified. These genes were modulated by the receptor either positively or negatively (12,(37)(38)(39)(40)(41)(42)(43), suggesting the pivotal roles of ERR␣1 in a variety of pathways during differentiation, development, and homeostasis.…”

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confidence: 99%

Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Zhang

Teng

2000

Journal of Biological Chemistry

130

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“…20). It also modulates expression of the estrogen-responsive genes lactoferrin (4), osteopontin (21), and even ERRa itself (also called ESRRA; refs. 22,23).…”

Section: Introductionmentioning

confidence: 99%

“…The effect of ERRa1 binding to a transcriptional response element can be either negative or positive depending on the specific cell type (8) and promoter context (24). For example, ERRa1 downmodulates E 2 -induced transcription in ERa-positive human mammary carcinoma MCF-7 cells by an active mechanism (8), yet activates gene transcription in ERa-negative human mammary carcinoma SK-BR-3 cells (19) and a variety of other cell lines, including human cervical carcinoma HeLa cells (8), human endometrial RL95-2 cells (4), human embryonic kidney 293 cells (21), and rat ROS 17/2.8 osteosarcoma cells (21).…”

Section: Introductionmentioning

confidence: 99%

Estrogen-Related Receptor α1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway

Ariazi

Kraus

Farrell

et al. 2007

Molecular Cancer Research

103

105

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We previously showed that (a) estrogen-related receptor A1 (ERRA1) down-modulates estrogen receptor (ER) -stimulated transcription in low ErbB2 -expressing MCF-7 mammary carcinoma cells, and (b) ERRA and ErbB2 mRNA levels positively correlate in clinical breast tumors. We show here that ERRA1 represses ERA-mediated activation in MCF-7 cells because it failed to recruit the coactivator glucocorticoid receptor interacting protein 1 (GRIP1) when bound to an estrogen response element. In contrast, ERRA1 activated estrogen response element -and ERR response element -mediated transcription in ERA-positive, high ErbB2 -expressing BT-474 mammary carcinoma cells, activation that was enhanced by overexpression of GRIP1. Likewise, regulation of the endogenous genes pS2, progesterone receptor, and ErbB2 by ERRA1 reflected the cell type -specific differences observed with our reporter plasmids. Importantly, overexpression of activated ErbB2 in MCF-7 cells led to transcriptional activation, rather than repression, by ERRA1. Two-dimensional PAGE of radiophosphate-labeled ERRA1 indicated that it was hyperphosphorylated in BT-474 relative to MCF-7 cells; incubation of these cells with anti-ErbB2 antibody led to reduction in the extent of ERRA1 phosphorylation. Additionally, mitogen-activated protein kinases (MAPK) and Akts, components of the ErbB2 pathway, phosphorylated ERRA1 in vitro. ERRA1-activated transcription in BT-474 cells was inhibited by disruption of ErbB2/epidermal growth factor receptor signaling with trastuzumab or gefitinib or inactivation of downstream components of this signaling, MAPK kinase/MAPK, and phosphatidylinositol-3-OH kinase/ Akt, with U0126 or LY294002, respectively. Thus, ERRA1 activities are regulated, in part, via ErbB2 signaling, with ERRA1 likely positively feedback-regulating ErbB2 expression. Taken together, we conclude that ERRA1 phosphorylation status shows potential as a biomarker of clinical course and antihormonal-and ErbB2-based treatment options, with ERRA1 serving as a novel target for drug development. (Mol Cancer Res 2007;5(1):71 -85)

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“…Expression of OPN is known to be in¯uenced by a number of di erent factors, including hormones, growth factors, tumor promoters, and oncogenes (Denhardt and Guo, 1993;Denhardt and Noda, 1998;Manji et al, 1998;Sato et al, 1998;Vanacker et al, 1998). The regulation of OPN expression appears to be exerted largely at the level of transcription (Denhardt and Noda, 1998) and the OPN promoter region, speci®cally the 5' upstream sequence of the human OPN gene (up to base pair 7250), is highly conserved among the human, murine, and porcine genes (Hijiya et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of the human osteopontin promoter: functional analysis and DNA-protein interactions

et al. 2000

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Synthesis of cell attachment proteins and cytokines, such as osteopontin (OPN), can promote tumor cell remodeling of the extracellular matrix into an environment that promotes tumor cell attachment and migration. We investigated the transcriptional regulation of OPN in the U-251MG and U-87MG human malignant astrocytoma cell lines. Deletion and mutagenesis analyses of the OPN promoter region identi®ed a proximal promoter element (724 to 794 relative to the transcription initiation site) that is essential for maintaining high levels of OPN expression in the tumor cells. This element, designated RE-1, consists of two cis-acting elements, RE-1a (755 to 786) and RE-1b (722 to 745), which act synergistically to regulate the activity of the OPN promoter. Gel shift assays using nuclear extracts of U-251MG cells demonstrated that RE-1a contains binding sites for transcription factors Sp1, the glucocorticoid receptor, and the E-box-binding factors, whereas RE-1b contains a binding site for the octamer motif-binding protein (OCT-1/OCT-2). Inclusion of antibodies directed toward Myc and OCT-1 in the gel shift assays indicated that Myc and OCT-1 participate in forming DNAprotein complexes on the RE-1a and RE-1b elements, respectively. Our results identify two previously unrecognized elements in the OPN promoter that act synergistically to promote upregulation of OPN synthesis by tumor cells but are regulated by di erent transcription factors. Oncogene (2000) 19, 5801 ± 5809.

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Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

Cited by 89 publications

References 24 publications

Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Estrogen-Related Receptor α1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway

Transcriptional regulation of the human osteopontin promoter: functional analysis and DNA-protein interactions

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