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Hepatocyte nuclear factor-4alpha interacts with other hepatocyte nuclear factors in regulating transthyretin gene expression.

Authors: Wang, Z  Burke, PA 
Citation: Wang Z and Burke PA, FEBS J. 2010 Oct;277(19):4066-75. doi: 10.1111/j.1742-4658.2010.07802.x. Epub 2010 Aug 23.
Pubmed: (View Article at PubMed) PMID:20735474
DOI: Full-text: DOI:10.1111/j.1742-4658.2010.07802.x

Transthyretin is a negative acute phase protein whose serum level decreases during the acute phase response. Transthyretin gene expression in the liver is regulated at the transcriptional level, and is controlled by hepatocyte nuclear factor (HNF)-4alpha and other HNFs. The site-directed mutagenesis of HNF-4, HNF-1, HNF-3 and HNF-6 binding sites in the transthyretin proximal promoter dramatically decreases transthyretin promoter activity. Interestingly, the mutation of the HNF-4 binding site not only abolishes the response to HNF-4alpha, but also reduces significantly the response to other HNFs. However, mutation of the HNF-4 binding site merely affects the specific binding of HNF-4alpha, but not other HNFs, suggesting that an intact HNF-4 binding site not only provides a platform for specific interaction with HNF-4alpha, but also facilitates the interaction of HNF-4alpha with other HNFs. In a cytokine-induced acute phase response cell culture model, we observed a significant reduction in the binding of HNF-4alpha, HNF-1alpha, HNF-3beta and HNF-6alpha to the transthyretin promoter, which correlates with a decrease in transthyretin expression after injury. These findings provide new insights into the mechanism of the negative transcriptional regulation of the transthyretin gene after injury caused by a decrease in the binding of HNFs and a modulation in their coordinated interactions.


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CRRD Object Information
CRRD ID: 8553707
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.