Abstract
The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of nuclear receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the nuclear receptor superfamily, including the orphan receptors SF-1 and LRH-1, and the bile acid receptor FXR. We have found that the SHP promoter is also activated by the estrogen receptor-related receptor gamma (ERRgamma) but not the related ERRalpha and ERRbeta isoforms. SHP and ERRgamma mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRgamma transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRalpha and ERRbeta activity on this element indicating that the lack of activity of ERRalpha and -beta may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these receptors on different response elements. SHP inhibits ERRgamma transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRgamma and the previously described N-terminal receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRgamma activity. Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs.
Highlights
The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of nuclear receptors and represses their transcriptional activity
Activation of the SHP Gene Promoter by ERR␥, but Not ERR␣ or ERR—Since a previous report demonstrated that SF-1 activates the SHP gene promoter via five characterized SF-1 response elements (SF-1RE) [16] and SF-1 and ERR family members share similar DNA binding characteristics [23, 34], we investigated whether ERR family members can regulate the SHP gene promoter
SHP is expressed in additional tissues, including heart, small intestine, stomach, epididymus, and prostate, several of which express the orphan receptor ERR␥
Summary
Interrupted by an intron and is located on human chromosome 1 at position 1p36.1 [12]. Later studies with more sensitive approaches have demonstrated the presence of SHP mRNA in a wide variety of tissues, with highest expression in heart, brain, liver, lung, and adrenal gland [11]. SHP is coexpressed with SF-1 or LRH-1 only in gonads, adrenal gland, and liver, indicating that other transcription factors are involved in SHP gene expression in other tissues, such as pancreas, heart, and brain. A recent report has demonstrated the binding of the synthetic estrogen analogue diethylstilbestrol to the ERR subfamily members [18]. In this case, diethylstilbestrol acts as an inverse agonist by disrupting ERR-coactivator interaction [18]. We conclude that ERR␥ is a component of a new potential autoregulatory loop controlling SHP gene expression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
