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MBC in Press, published online ahead of print February 21, 2006
Mol. Biol. Cell 10.1091/mbc.E05-10-0979

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Submitted on October 25, 2005
Revised on December 14, 2005
Accepted on February 1, 2006

Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor {alpha} Transcriptional Activity

Guang-Hui Liu,* Jing Qu,* and Xun Shen*{dagger}

*Institute of Biophysics and Graduate School, Chinese Academy of Sciences, Beijing 100101, China; {dagger}Division of Nitric Oxide and Inflammatory Medicine, E-Institutes of Shanghai Universities (Shanghai University of Traditional Chinese Medicine), Shanghai, China

Monitoring Editor: William Tansey

PPAR{alpha}, a member of the nuclear receptor superfamily, and thioredoxin, a critical redox-regulator in cells, were found to form a negative feedback loop, which autoregulates transcriptional activity of PPAR{alpha}. Thioredoxin was identified as a target gene of PPAR{alpha}. Activation of PPAR{alpha} leads to increase of thioredoxin expression as well as its translocation from cytoplasm to nucleus, while ectopic overexpression of thioredoxin in the nucleus dramatically inhibited both constitutive and ligand-dependent PPAR{alpha} activation. As PPAR{alpha}-target genes, the expression of muscle carnitine palmitoyltransferase I, medium chain acyl CoA dehydrogenase, and apolipoprotein A-I were significantly down-regulated by nucleus-targeted thioredoxin at transcriptional or protein level. The suppression of PPAR{alpha} transcriptional activity by Trx could be enhanced by overexpression of thioredoxin reductase or knockdown of thioredoxin interacting protein, but abrogated by mutating the redox-active sites of thioredoxin. Mammalian one-hybrid assays showed that thioredoxin inhibited PPAR{alpha} activity by modulating its AF-1 transactivation domain. It was also demonstrated by electrophoretic mobility-shift assay that thioredoxin inhibited the binding of PPAR{alpha} to the PPAR-response element. Together, it is speculated that the reported negative-feedback loop may be essential for maintaining the homeostasis of PPAR{alpha} activity.

Address correspondence to: Xun Shen (shenxun{at}sun5.ibp.ac.cn)




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[Abstract] [Full Text] [PDF]


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