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Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region.

ABSTRACT: The transcription of the human UCP3 (uncoupling protein-3) gene in skeletal muscle is tightly regulated by metabolic signals related to fatty acid availability. However, changes in thyroid status also modulate UCP3 gene expression, albeit by unknown mechanisms. We created transgenic mice bearing the entire human UCP3 gene to investigate the effect of thyroid hormones on human UCP3 gene expression. Treatment of human UCP3 transgenic mice with thyroid hormones induced the expression of the human gene in skeletal muscle. In addition, transient transfection experiments demonstrate that thyroid hormones activate the transcription of the human UCP3 gene promoter when MyoD and the TR (thyroid hormone receptor) were co-transfected. The action of thyroid hormones on UCP3 gene transcription is mediated by the binding of the TR to a proximal region in the UCP3 gene promoter that contains a direct repeat structure. An intact DNA sequence of this site is required for thyroid hormone responsiveness and TR binding. Chromatin immunoprecipitation assays revealed that the TR binds this element in vivo. The murine Ucp3 gene promoter was also dependent on MyoD and responsive to thyroid hormone in transient transfection assays. However, it was much less sensitive to thyroid hormone than the human UCP3 promoter. In summary, UCP3 gene transcription is activated by thyroid hormone treatment in vivo, and this activation is mediated by a TRE (thyroid hormone response element) in the proximal promoter region. Such regulation suggests a link between UCP3 gene expression and the effects of thyroid hormone on mitochondrial function in skeletal muscle.

SUBMITTER: Solanes G

PROVIDER: S-EPMC1134869 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region.

Solanes Gemma G Pedraza Neus N Calvo Verónica V Vidal-Puig Antonio A Lowell Bradford B BB Villarroya Francesc F

The Biochemical journal 20050301 Pt 3

The transcription of the human UCP3 (uncoupling protein-3) gene in skeletal muscle is tightly regulated by metabolic signals related to fatty acid availability. However, changes in thyroid status also modulate UCP3 gene expression, albeit by unknown mechanisms. We created transgenic mice bearing the entire human UCP3 gene to investigate the effect of thyroid hormones on human UCP3 gene expression. Treatment of human UCP3 transgenic mice with thyroid hormones induced the expression of the human g ...[more]

PMID: 15496137

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Project description:Uncoupling protein (UCP) 2 is a member of the uncoupling-protein family, and it appears to function as an uncoupler of oxidative phosphorylation. To identify cis-acting regulatory elements controlling this gene's expression, we cloned an approx. 6.2-kb region upstream from the translation-initiation site of the mouse UCP2 gene and analysed its transcription activity using chimaeric mouse UCP2 promoter-placental-alkaline-phosphatase (PLAP) reporter-gene constructs. Sequence analysis showed that the 5'-flanking region of the mouse UCP2 gene was not similar to those of mouse UCP1 or UCP3. For the mouse UCP2, the region near the transcription-initiation site lacked the typical TATA box, but was GC-rich, resulting in presence of several potential specificity protein 1 (Sp-1), activator protein (AP)-1 and AP-2 binding sites. The putative regulatory motifs for muscle-regulatory protein (MyoD), brown-fat regulatory element, CCAAT box, cAMP-response element and Y box were also found in the mouse UCP2 promoter region by computer-assisted analysis. From the results of Northern-blot analysis and transient expression assay, we found that the mouse UCP2 gene responded to the cAMP-dependent protein kinase alpha-catalytic subunit signal activation at the transcription level. Additionally, deletion analysis of the UCP2 promoter-PLAP constructs indicated that the minimal region exhibiting the promoter activity was located between nt -33 and +100, and that a strong enhancer was present within 601 bp of the 5'-promoter region. In particular, the region from nt -233 to -34 significantly induced PLAP activity in the cell lines derived from various tissues and in the primary culture cells of rat brown adipose tissue, suggesting that this region is most important for the ubiquitous expression of mouse UCP2 mRNA. Furthermore, it was shown that two silencer elements were involved in the mouse UCP2 gene; one was located between nt -2746 and -602, and the other was identified in intron 1. These regions deprived the enhancer of the ability to induce PLAP activity. This study shows a fundamental role for positive and negative cis-acting DNA elements in regulating the basal and cAMP-induced transcription activity of the mouse UCP2 gene.

Dataset Information

Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region.

Publications

Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region.

Similar Datasets

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