Human Tribbles homolog 1 functions as a negative  regulator of retinoic acid receptor.
Tribbles encode an evolutionarily conserved protein family that regulates cell proliferation, motility, metabolism and oncogenic transformation. Emerging evidence suggests that Tribbles function as adaptor or scaffold proteins to facilitate the degradation of their target proteins and to control the activation of various key signaling pathways. In this study, we uncover a novel function of human Tribbles homolog 1 (Trib1) as a regulator of retinoic acid receptor (RAR) signaling. We show that shRNA-mediated knockdown of Trib1 promotes transcriptional activity of RARs, leading to enhanced expression of endogenous RAR-target genes. Moreover, our results show that Trib1 directly interacts with RARα and retinoid X receptor-α (RXRα) through its kinase-like domain. Consistently, Trib1 colocalizes with RARα and RXRα in the nucleus. Biochemical analyses show that the ligand-binding domain (LBD) of RARα mediates the interaction with Trib1. Ligand treatment, however, does not affect the binding of Trib1 to RARα/RXRα. Furthermore, a putative LXXLL motif, which is a potential LBD-binding site and locates in the kinase-like domain of Trib1, is not required for the binding.These results suggest a unique feature of the binding. Taken together, these results suggest that Trib1 functions as a negative regulator of RARs and shed new light on the molecular mechanisms for nuclear receptor-mediated transcriptional repression.
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Masamichi
M
Imajo
Eisuke
E
Nishida
D018938:Caco-2 Cells; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000037:antagonists & inhibitors; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases