Abstract
Recently, we reported the cloning of the nuclear orphan receptor TAK1. In this study, we characterized the sequence requirements for optimal TAK1 binding and analyzed the repression of the peroxisome proliferator-activated receptor alpha (PPARalpha) signaling pathway by TAK1. Site selection analysis showed that TAK1 has the greatest affinity for direct repeat-1 response elements (RE) containing AGGTCAAAGGTCA (TAK1-RE) to which it binds as a homodimer. TAK1 is a very weak inducer of TAK1-RE-dependent transcriptional activation. We observed that TAK1, as PPARalpha, is expressed within rat hepatocytes and is able to bind the peroxisome proliferator response elements (PPREs) present in the promoter of the PPARalpha target genes rat enoyl-CoA hydratase (HD) and peroxisomal fatty acyl-CoA oxidase (ACOX). TAK1 is unable to induce PPRE-dependent transcriptional activation and represses PPARalpha-mediated transactivation through these elements in a dose-dependent manner. Two-hybrid analysis showed that TAK1 does not form heterodimers with either PPARalpha or retinoid X receptor (RXRalpha), indicating that this repression does not involve a mechanism by which TAK1 titrates out PPARalpha or RXRalpha from PPAR.RXR complexes. Further studies demonstrated that the PPARalpha ligand 8(S)-hydroxyeicosatetraenoic acid strongly promotes the interaction of PPARalpha with the co-activator RIP-140 but decreases the interaction of PPARalpha with the co-repressor SMRT. In contrast, TAK1 interacts with RIP-140 but not with SMRT and competes with PPARalpha for RIP-140 binding. These observations indicated that the antagonistic effects of TAK1 on PPARalpha.RXRalpha transactivation act at least at two levels in the PPARalpha signaling pathway: competition of TAK1 with PPARalpha.RXR for binding to PPREs as well as to common co-activators, such as RIP-140. Our results suggest an important role for TAK1 in modulating PPARalpha-controlled gene expression in hepatocytes.
Highlights
The nuclear receptor superfamily is comprised of a class of ligand-dependent transcription factors that regulate gene expression during many biological processes, including development, cellular proliferation, and differentiation [1,2,3,4,5,6]
We show that TAK1 is highly expressed in rat hepatocytes that express several other nuclear receptors, including the peroxisome proliferator-activated receptor ␣ (PPAR␣) and retinoid X receptor (RXR) [6, 32,33,34,35,36,37]
We showed that TAK1 and PPAR␣ are co-expressed in hepatocytes and that both receptors recognize several DR1s, including TAK1-response element (RE) and PPREs of the acyl-CoA oxidase (ACOX) and hydroxyacylCoA dehydrogenase (HD) genes
Summary
Vol 273, No 18, Issue of May 1, pp. 10948 –10957, 1998 Printed in U.S.A. Regulation of Peroxisome Proliferator-activated Receptor ␣-Induced Transactivation by the Nuclear Orphan Receptor TAK1/TR4*. The nuclear receptor superfamily is comprised of a class of ligand-dependent transcription factors that regulate gene expression during many biological processes, including development, cellular proliferation, and differentiation [1,2,3,4,5,6]. TAK1 inhibited the PPRE-dependent transcriptional activation mediated by PPAR␣1⁄7RXR␣ heterodimers We demonstrated that this repression did not involve a mechanism by which TAK1 titrates out PPAR␣ or RXR␣ from PPAR␣1⁄7RXR complexes but was due to competition of TAK1 with PPAR␣1⁄7RXR␣ for binding to PPREs and common co-activators, such as RIP140. These results suggest an important role for TAK1 in modulating PPAR␣-controlled gene expression in the liver
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