Abstract
The yeast two-hybrid system was used to isolate novel cellular factors that interact with the mouse peroxisome proliferator-activated receptor alpha (PPARalpha). One of the interacting clones isolated encoded LXRalpha, a recently described human orphan nuclear hormone receptor. LXRalpha bound directly to PPARalpha, as well as to the common heterodimerization partner 9-cis-retinoic acid receptor (RXRalpha). LXRalpha did not form a DNA binding complex with PPARalpha on synthetic hormone response elements composed of direct repeats of the TGACCT consensus half-site or on naturally occurring peroxisome proliferator response elements (PPREs) or LXRalpha response elements. However, LXRalpha inhibited binding of PPARalpha/RXRalpha heterodimers to PPREs, and coexpression of LXRalpha in mammalian cells antagonized peroxisome proliferator signaling mediated by PPARalpha/RXRalpha in vivo. These findings identify a novel partner for PPARalpha and suggest that LXRalpha plays a role in modulating PPAR-signaling pathways in the cell.
Highlights
PPARs activate expression of target genes by recognizing peroxisome proliferator response elements (PPREs) composed of TGACCT-related direct repeats that are spaced by one nucleotide (DR1) [11, 12]
Specific DNA binding is manifested through heterodimerization with the 9-cis-retinoic acid receptor, RXR␣ [13, 14], another member of the nuclear hormone receptor superfamily that serves as a heterodimerization partner for thyroid hormone, retinoic acid, and vitamin D receptors [1]
Interaction Cloning of PPAR-interacting Factors—Yeast harboring GBD-N⌬mPPAR␣ were used to screen a HeLa cell cDNA library fused to the GAL4 transactivation domain
Summary
PPARs activate expression of target genes by recognizing peroxisome proliferator response elements (PPREs) composed of TGACCT-related direct repeats that are spaced by one nucleotide (DR1) [11, 12]. One mPPAR␣-interacting factor isolated was identified as LXR␣, a recently described human orphan nuclear hormone receptor that appears to be involved in a novel retinoid signaling pathway [20].
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