SHP (small heterodimer partner; NR0B2) is an atypical orphan NR (nuclear receptor) that functions as a transcriptional co-repressor by interacting with a diverse set of NRs and transcriptional factors. HNF-6 (hepatocyte nuclear factor-6) is a key regulatory factor in pancreatic development, endocrine differentiation and the formation of the biliary tract, as well as glucose metabolism. In this study, we have investigated the function of SHP as a putative repressor of HNF-6. Using transient transfection assays, we have shown that SHP represses the transcriptional activity of HNF-6. Confocal microscopy revealed that both SHP and HNF-6 co-localize in the nuclei of cells. SHP physically interacted with HNF-6 in protein–protein association assays in vitro. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays demonstrated that SHP inhibits the DNA-binding activity of HNF-6 to an HNF-6-response element consensus sequence, and the HNF-6 target region of the endogenous G6Pase (glucose 6-phosphatase) promoter respectively. Northern blot analysis of HNF-6 target genes in cells infected with adenoviral vectors for SHP and SHP siRNAs (small inhibitory RNAs) indicated that SHP represses the expression of endogenous G6Pase and PEPCK (phosphoenolpyruvate carboxykinase). Our results suggest that HNF-6 is a novel target of SHP in the regulation of gluconeogenesis.
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Research Article|
July 15 2008
Orphan nuclear receptor SHP interacts with and represses hepatocyte nuclear factor-6 (HNF-6) transactivation
Yong-Soo Lee;
Yong-Soo Lee
*Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
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Don-Kyu Kim;
Don-Kyu Kim
*Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
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Yong Deuk Kim;
Yong Deuk Kim
*Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
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Ki Cheol Park;
Ki Cheol Park
†Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, Republic of Korea
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Minho Shong;
Minho Shong
†Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, Republic of Korea
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Hyun-A Seong;
Hyun-A Seong
‡Department of Biochemistry, Biotechnology Research Institute, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea
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Hyun Jung Ha;
Hyun Jung Ha
‡Department of Biochemistry, Biotechnology Research Institute, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea
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Hueng-Sik Choi
Hueng-Sik Choi
1
*Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
1To whom correspondence should be addressed (email hsc@chonnam.ac.kr).
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Publisher: Portland Press Ltd
Received:
December 05 2007
Revision Received:
March 04 2008
Accepted:
May 07 2008
Accepted Manuscript online:
May 10 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 413 (3): 559–569.
Article history
Received:
December 05 2007
Revision Received:
March 04 2008
Accepted:
May 07 2008
Accepted Manuscript online:
May 10 2008
Citation
Yong-Soo Lee, Don-Kyu Kim, Yong Deuk Kim, Ki Cheol Park, Minho Shong, Hyun-A Seong, Hyun Jung Ha, Hueng-Sik Choi; Orphan nuclear receptor SHP interacts with and represses hepatocyte nuclear factor-6 (HNF-6) transactivation. Biochem J 1 August 2008; 413 (3): 559–569. doi: https://doi.org/10.1042/BJ20071637
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