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Am J Physiol Cell Physiol (December 4, 2002). doi:10.1152/ajpcell.00394.2002
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Articles in PresS, published online ahead of print December 4, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00394.2002
Submitted on August 28, 2002
Accepted on November 26, 2002

Serine/Threonine Phosphorylation Regulates HNF-4{alpha} Dependent Redox Mediated iNOS Expression in Hepatocytes

Hongtao Guo1, Junping Wei1, Yusuke Inoue2, Frank C Gonzalez2, and Paul C Kuo1*

1 Surgery, Duke University, Durham, NC, USA
2 NCI, NIH, Bethesda, MD, USA

* To whom correspondence should be addressed. E-mail: kuo00004{at}mc.duke.edu.

Background and Rationale: Nitric oxide (NO), endogenously synthesized by inducible NO synthase (iNOS), serves anti-oxidant and anti-apoptotic functions in settings characterized by oxidative stress and pro-inflammatory cytokines such as, sepsis and shock. However, the redox sensitive mechanisms regulating hepatocyte expression of iNOS are largely unknown. Results: In interleukin-1{beta} (IL-1{beta}) stimulated hepatocytes exposed to superoxide, we demonstrate that hepatocyte nuclear factor-4{alpha} (HNF-4{alpha}) acts as an enhancer of redox-associated hepatocyte iNOS expression at the level of protein, mRNA, and promoter activation. In the absence of HNF-4{alpha}, this redox-mediated enhancement is ablated. HNF-4{alpha} functional activity is associated with a unique serine/threonine kinase-mediated phosphorylation pattern. This suggests that a redox-sensitive kinase pathway targets HNF-4{alpha} to augment hepatocyte iNOS expression. Previous studies have not addressed a redox-dependent kinase signalling pathway which targets HNF-4{alpha} and enhances hepatocyte iNOS gene transcription. Conclusions: A unique pattern of phosphorylation determines HNF-4{alpha} activity as a trans-enhancer of IL-1{beta} mediated hepatocyte iNOS expression in the presence of oxidative stress.




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