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Submitted on August 18, 2003
Accepted on January 23, 2004
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Kwangju 500-757, Republic of Korea, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA, Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea, Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejon 301-721, Republic of Korea, and Department of Endocrinology, Diabetes and Rheumatology, Division of Bioregulatory Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu-city, Gifu 500-8705, Japan.
* To whom correspondence should be addressed. E-mail: hsc{at}chonnam.chonnam.ac.kr.
Small Heterodimer Partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain (DBD) and represses the transcriptional activity of various nuclear receptors. In this study, we examined the novel crosstalk between SHP and BETA2/NueroD, a basic helix-loop-helix (bHLH) transcription factor. In vitro and in vivo protein interaction studies showed that SHP physically interacts with BETA2/NeuroD, but not its heterodimer partner E47. Moreover, confocal microscopic study and immunostaining results demonstrated that SHP colocalized with BETA2 in islets of mouse pancreas. SHP inhibited BETA2/NeuroD-dependent transactivation of an E-box reporter, while SHP was unable to repress the E47-mediated transactivation and the E-box mutant reporter activity. In addition, SHP repressed the BETA2-dependent activity of glucokinase (GK) and cdk inhibitor p21 gene promoters. Gel shift and in vitro protein competition assays indicated that SHP inhibits neither dimerization nor DNA binding of BETA2 and E47. Rather, SHP directly repressed BETA2 transcriptional activity and p300-enhanced BETA2/NeuroD transcriptional activity by inhibiting interaction between BETA2 and coactivator p300. We also showed that C-terminal repression domain within SHP is also required for BETA2 repression. However, inhibition of BETA2 activity was not observed by naturally occurring human SHP mutants that cannot interact with BETA2/NeuroD. Taken together, these results suggest that SHP acts as a novel corepressor for bHLH transcription factor BETA2/NeuroD by competing with coactivator p300 for binding to BETA2/NeuroD and by its direct transcriptional repression function.
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