This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xu, P.-L. Articles by Wang, Y. Search for Related Content PubMed PubMed Citation Articles by Xu, P.-L. Articles by Wang, Y.

Molecular Mechanism for the Potentiation of the Transcriptional Activity of Human Liver Receptor Homolog 1 by Steroid Receptor Coactivator-1

State Key Laboratory of Molecular Biology (P.-L.X., S.-F.S., Y.-Y.K., Q.Z., M.L., Y.-H.X., Y.W.) and Key Laboratory of Proteomics (Y.-Q.L., J.-P.D.), Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Address all correspondence and requests for reprints to: Yuan Wang or You-Hua Xie or Jian-Ping Ding, Institute of Biochemistry and Cell Biology, 320 Yueyang Road, Shanghai 200031, China. E-mail:wangy{at}sibs.ac.cn (Y.W.), yhxie{at}sibs.ac.cn (Y.-H.X.), jpding{at}sibs.ac.cn (J.-P.D.).

The liver receptor homolog 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 (h) LRH-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 (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 cholesterol 7--hydroxylase promoter and increases the transcription of the endogenous cholesterol 7--hydroxylase 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 activation function-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/transcriptional intermediary factor 2 or SRC-3/acetyltransferase. Moreover, transcriptional intermediary factor 2 and acetyltransferase 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   LRH-1

Coregulators:   p300  |  SRC-1  |  GRIP1  |  AIB1  |  NCOR  |  SMRT

This article has been cited by other articles:

				T. Kanayama, M. Arito, K. So, S. Hachimura, J. Inoue, and R. Sato Interaction between Sterol Regulatory Element-binding Proteins and Liver Receptor Homolog-1 Reciprocally Suppresses Their Transcriptional Activities J. Biol. Chem., April 6, 2007; 282(14): 10290 - 10298. [Abstract] [Full Text] [PDF]

				W. Zheng, J. Yang, Q. Jiang, Z. He, and L. M Halvorson Liver receptor homologue-1 regulates gonadotrope function J. Mol. Endocrinol., February 1, 2007; 38(2): 207 - 219. [Abstract] [Full Text] [PDF]

				G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors Pharmacol. Rev., December 1, 2006; 58(4): 798 - 836. [Abstract] [Full Text] [PDF]

				C. P. Martinez-Jimenez, M. J. Gomez-Lechon, J. V. Castell, and R. Jover Underexpressed Coactivators PGC1{alpha} AND SRC1 Impair Hepatocyte Nuclear Factor 4{alpha} Function and Promote Dedifferentiation in Human Hepatoma Cells J. Biol. Chem., October 6, 2006; 281(40): 29840 - 29849. [Abstract] [Full Text] [PDF]

				Y.-K. Lee, Y.-H. Choi, S. Chua, Y. J. Park, and D. D. Moore Phosphorylation of the Hinge Domain of the Nuclear Hormone Receptor LRH-1 Stimulates Transactivation J. Biol. Chem., March 24, 2006; 281(12): 7850 - 7855. [Abstract] [Full Text] [PDF]

				Y. Li, M. Choi, K. Suino, A. Kovach, J. Daugherty, S. A. Kliewer, and H. E. Xu Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner PNAS, July 5, 2005; 102(27): 9505 - 9510. [Abstract] [Full Text] [PDF]