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Title:
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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
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Author:
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Solanes, Gemma; Pedraza González, Neus; Calvo Garrido, Verónica; Vidal Puig, Antonio; Lowell, Bradford B.; Villarroya, Francesc
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Notes:
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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 TRbinds
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.
This work was supported by grant SAF2002-03648 from Ministerio de Ciencia y Tecnolog´ıa, Fundaci´o la Marat´o de TV3 and grant C03/08 from Instituto Carlos III, Ministerio de Sanidad y Consumo, Spain. G. S. is under the ‘Ramon y Cajal’ Investigator program. We thank Dr R. Evans, Dr H. H. Samuels, Dr H. C. Towle and Dr A. B. Lassar for kindly supplying expression vectors. |
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Subject(s):
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-Promoter regulation
-Thyroid hormone
-Transgenic mouse
-Uncoupling protein-3 (UCP3) |
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Rights:
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(c) Biochemical Society, 2005
info:eu-repo/semantics/restrictedAccess |
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Document type:
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article
publishedVersion |
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Published by:
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Portland Press
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