title: Gene repressive activity of RIP140 through direct interaction with CDK8.
abstract: Receptor interacting protein 140 (RIP140) is a coregulator for numerous nuclear receptors and transcription factors and primarily exerts gene-repressive activities on various target genes. We previously identified a spectrum of posttranslational modifications on RIP140 that augment its property and biological activity. In T(3)-triggered biphasic regulation of cellular retinoic acid binding protein 1 (Crabp1) gene along the course of fibroblast-adipocyte differentiation, we found TRAP220(MED1) critical for T(3)-activated chromatin remodeling whereas RIP140 essential for T(3)-repressive chromatin remodeling of this gene promoter. In this current study, we aim to examine whether and how RIP140 replaces TRAP220(MED1) on the CrabpI promoter in differentiating adipocyte cultures. We find increasing recruitment of RIP140 to this promoter, with corresponding reduction in TRAP220(MED1) recruitment during the T(3)-repressive phase. We also uncover direct interaction of RIP140 with cyclin-dependent kinase (CDK)8 through the amino terminus of RIP140, which is stimulated by lysine acetylation on RIP140. We further validate the biological activity of lysine acetylation-mimetic RIP140, which elicits a stronger repressive effect and more efficiently recruits CDK8 and confirm CDK8's function in recruiting repressive components, such as G9a, to the RIP140 complex on this promoter. This underlies the T(3)-triggered repression of CrabpI gene. This study illustrates a new gene-repressive mechanism of RIP140 that can affect the transcription machinery by directly interacting with CDK8.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Shawna D
authors.initials: SD
authors.lastname: Persaud
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Huang
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Park
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wei
mesh_terms: D041721:3T3-L1 Cells; D000107:Acetylation; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D047369:Chromatin Immunoprecipitation; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D005786:Gene Expression Regulation; D008239:Lysine / Q000378:metabolism; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism
chemical_list: C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D056971:Nuclear Receptor Co-Repressor 1; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D037021:Thyroid Hormone Receptors alpha; C082927:retinoic acid binding protein I, cellular; D056850:Cyclin-Dependent Kinase 8; D008239:Lysine