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Submitted on September 1, 2003
Accepted on May 3, 2004
State Key Laboratory of Molecular Biologyand Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
* To whom correspondence should be addressed. E-mail: wangy{at}sibs.ac.cn. * To whom correspondence should be addressed. E-mail: wangy{at}sibs.ac.cn. * To whom correspondence should be addressed. E-mail: wangy{at}sibs.ac.cn.
The liver receptor homologue 1 (LRH-1) belongs to the fushi tarazu factor 1 nuclear receptor subfamily and its biological functions are just being unveiled. The molecular mechanism for the transcriptional regulation by LRH-1 is not clear yet. In this report, we use mutagenesis and reporter gene assays to carry out a detailed analysis on the hinge region and the proximal ligand-binding domain (LBD) of human LRH-1 (hLRH-1) that possess important regulatory functions. Our results indicate that helix 1 of the LBD is essential for the activity of hLRH-1 and that the steroid receptor coactivator-1 (SRC-1) interacts directly with the LBD of hLRH-1 and significantly potentiates the transcriptional activity of hLRH-1. Cotransfection assays demonstrate that overexpressed SRC-1 potentiates hLRH-1 mediated activation of the CYP7A1 promoter and increases the transcription of the endogenous CYP7A1 in Huh7 cells. The interaction between SRC-1 and hLRH-1 assumes a unique pattern that involves primarily a region containing the glutamine-rich domain of SRC-1, and helix 1 and AF-2 of hLRH-1 LBD. Mutagenesis and molecular modeling studies indicate that, similar to mouse LRH-1, the coactivator-binding cleft of hLRH-1 LBD is not optimized. An interaction between helix 1 of hLRH-1 LBD and a region containing the glutamine-rich domain of SRC-1 can provide an additional stabilizing force and enhances the recruitment of SRC-1. Similar interaction is observed between hLRH-1 and SRC-2/TIF2 or SRC-3/ACTR. Moreover, TIF2 and ACTR also potentiate the transcriptional activity of hLRH-1, suggesting a functional redundancy among SRC family members. These findings collectively demonstrate an important functional role of helix 1 in cofactor recruitment and reveal a novel molecular mechanism of transcriptional regulation and cofactor recruitment mediated by hLRH-1.
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