title: TNIP1 is a corepressor of agonist-bound PPARs.
abstract: Nuclear receptor (NR) coregulators include coactivators, contributing to holoreceptor transcriptional activity, and corepressors, mediating NR target gene silencing in the absence of hormone. We identified an atypical NR coregulator, TNFα-induced protein 3-interacting protein 1 (TNIP1), from a peroxisome proliferator activated receptor (PPAR) α screen of a human keratinocyte cDNA library. TNIP1's complex nomenclature parallels its additional function as an NF-κB inhibitor. Here we show TNIP1 is an atypical NR corepressor using two-hybrid systems, biochemical studies, and receptor activity assays. The requirements for TNIP1-PPAR interaction are characteristic for coactivators; however, TNIP1 partially decreases PPAR activity. TNIP1 has separable transcriptional activation and repression domains suggesting a modular nature to its overall effect. It may provide a means of lowering receptor activity in the presence of ligand without total loss of receptor function. TNIP1's multiple roles and expression in several cell types suggest its regulatory effect depends on its expression level and the expression of other regulators in NR and/or NF-κB signaling pathways. As a NR coregulator, TNIP1 targeting agonist-bound PPAR and reducing transcriptional activity offers control of receptor signaling not available from typical corepressors and may contribute to combinatorial regulation of transcription.
authors.affiliation: Graduate Program in Pharmacology & Toxicology, University of Connecticut, Storrs, 06269-3092, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Flores
authors.forename: Igor
authors.initials: I
authors.lastname: Gurevich
authors.forename: Carmen
authors.initials: C
authors.lastname: Zhang
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Ramirez
authors.forename: Taylor R
authors.initials: TR
authors.lastname: Devens
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Aneskievich
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D056970:Co-Repressor Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015723:Gene Library; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D015533:Transcriptional Activation
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D047492:Peroxisome Proliferator-Activated Receptors; C117046:TNIP1 protein, human