title: FHL2 protein is a novel co-repressor of nuclear receptor Nur77.
abstract: The three members of the NR4A orphan nuclear receptor subfamily Nur77, Nurr1, and NOR-1, regulate a variety of biological functions including vascular disease and metabolism. In this study, we identified Four and a half LIM domains protein-2 (FHL2) as a novel interacting protein of NR4A nuclear receptors by yeast two-hybrid screen and co-immunoprecipitation studies. Each of the four LIM domains of FHL2 can bind Nur77, and both the amino-terminal domain and the DNA binding domain of Nur77 are involved in the interaction between FHL2 and Nur77. FHL2 represses Nur77 transcriptional activity in a dose-dependent manner, and short hairpin RNA-mediated knockdown of FHL2 results in increased Nur77 transcriptional activity. ChIP experiments on the enolase3 promoter revealed that FHL2 inhibits the association of Nur77 with DNA. FHL2 is highly expressed in human endothelial and smooth muscle cells, but not in monocytes or macrophages. To substantiate functional involvement of FHL2 in smooth muscle cell physiology, we demonstrated that FHL2 overexpression increases the growth of these cells, whereas FHL2 knockdown results in reduced DNA synthesis. Collectively, these studies suggest that association of FHL2 with Nur77 plays a pivotal role in vascular disease.
authors: Department of Medical Biochemistry, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors: Kondababu
authors: K
authors: Kurakula
authors: Erik
authors: E
authors: van der Wal
authors: Dirk
authors: D
authors: Geerts
authors: Claudia M
authors: CM
authors: van Tiel
authors: Carlie J M
authors: CJ
authors: de Vries
mesh_terms: D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism
chemical_list: C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA; D010751:Phosphopyruvate Hydratase