tailieunhanh - Báo cáo khoa học: Hepatocyte nuclear factor-4a interacts with other hepatocyte nuclear factors in regulating transthyretin gene expression

Accumulation ofb-amyloid protein (Ab) is one of the most important pathological features of Alzheimer’s disease. Although Abinduces neurode-generation in the cortex and hippocampus through several molecular mech-anisms, few studies have evaluated the modulation of transcription factors during Ab-induced neurotoxicity. | Hepatocyte nuclear factor-4a interacts with other hepatocyte nuclear factors in regulating transthyretin gene expression Zhongyan Wang and Peter A. Burke Department of Surgery Boston University Schoolof Medicine MA USA Keywords acute phase response gene transcription hepatocyte nuclear factor HepG2 cell transthyretin Correspondence P. A. Burke Boston University Schoolof Medicine Boston MedicalCenter 850 Harrison Avenue Dowling 2 South Boston MA 02118 USA Fax 1 617 414 7398 Tel 1 617 414 8056 E-mail Received 15 April 2010 revised 2 July 2010 accepted 29 July 2010 doi 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 -4a 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-4a but also reduces significantly the response to other HNFs. However mutation of the HNF-4 binding site merely affects the specific binding of HNF-4a but not other HNFs suggesting that an intact HNF-4 binding site not only provides a platform for specific interaction with HNF-4a but also facilitates the interaction of HNF-4a with other HNFs. In a cytokine-induced acute phase response cell culture model we observed a significant reduction in the binding of HNF-4a HNF-1a HNF-3P and HNF-6a 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. Introduction .