Abstract
The orphan nuclear receptor TR2 functions as a constitutive activator for the endogenous retinoic acid receptor beta2 (RAR(beta2)) gene expression in P19 embryonal carcinoma cells and for reporters driven by the RAR(beta2) promoter in COS-1 cells. The activation of RAR(beta2) by TR2 is mediated by the direct repeat-5 (DR5) element located in the RAR(beta2) promoter. Furthermore, cAMP exerts an enhancing effect on the activation of RAR(beta2) by TR2, which is mediated by the cAMP response element located in the 5'-flanking region of the DR5. The constitutive activation function-1 (AF-1) of TR2 is mapped to amino acid residues 10-30 in its N-terminal A segment. A direct molecular interaction occurs between CREMtau and TR2, detected by co-immunoprecipitation, which is mediated by the N-terminal AB segment of TR2. In gel mobility shift assays, TR2 competes with P19 nuclear factor binding to the RAR(beta2) promoter, and TR2 and CREMtau bind simultaneously to this DNA fragment. The role of TR2 in the early events of RA signaling process is discussed.
Highlights
The mouse orphan receptor TR2 was isolated from an E8.5 embryonic cDNA library [11], and the gene was characterized [12]
In an attempt to determine the constitutive activity of TR2 on direct repeat-5 (DR5) reporters, i.e. its biological activity in the absence of RA, we set up experiments to examine the effects of TR2 expression on RA receptor 2 (RAR2) gene activities using both reporter and endogenous gene expression systems
The RAR2 promoter is activated by TR2 in the absence of RA, which can be enhanced by cAMP
Summary
CRE-DR5-TATA ϳCRE-DR5-TATA TATA CREM TR2, A-1/40 TR2, A-1/30 TR2, A-10/30 TR2, A-10/25. It is demonstrated that apo-TR2 functions as a constitutive activator for reporters driven by the RAR2 promoter containing the DR5 element, and overexpression of TR2 in P19 stem cells activates the endogenous RAR2 gene expression. CAMP exerts an enhancing effect on the activating function of TR2 on this promoter, which contains a CRE and a DR5. In gel mobility shift assays, TR2 competes with P19 nuclear factors binding to the RAR2 promoter, and TR2 and CREM bind simultaneously to this DNA fragment. We report these studies characterizing TR2 as a constitutive activator for the RAR2 promoter, which can be enhanced by cAMP
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