RIF-1, a novel nuclear receptor corepressor that associates with the nuclear matrix.
The retinoic acid receptors (RARs) are ligand-dependent transcription factors that play critical roles in cell differentiation, embryonic development, and tumor suppression. RAR transcriptional activities are mediated by a growing family of nuclear receptor (NR) coregulators. Here we report the cloning and characterization of a novel protein RIF1 (receptor interacting factor) that interacts with RARalpha in vivo and in vitro. RIF1 encodes a novel 739 amino acid protein that is ubiquitously expressed in a variety of tissues and cell lines. GST-pull down assays show that RIF1 also interacts with a number of other NRs. The interaction domain of RIF1 for RARalpha is located at the C-terminal region of RIF1, between amino acids 512 and 674. RIF1 is localized exclusively in the cell nucleus and specifically to the nuclear matrix. Mutation of the nuclear localization signal abolishes this nuclear localization and causes RIF1 to appear in the cytoplasm. Co-transfection of RIF1 with RAR causes RAR to localize to the nuclear matrix. RIF1 contains a strong transcriptional repression domain that robustly inhibits ligand-dependent transcriptional activation by RARalpha. This domain is located to the distal C-terminal 100 amino acids, distinct from the RARalpha-interaction and nuclear matrix-targeting domains. The transcriptional repression activity of RIF1 is mediated at least in part through direct recruitment of histone deacetylases. This study identifies RIF1 as a novel nuclear matrix transcription repressor, and suggests a potential role of RIF1 that regulates NR transcriptional activity.
Li
Hui Joyce
HJ
Molecular Cardiology Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. huijoyceli@yahoo.com
Haque
Zaffar K
ZK
Chen
Amy
A
Mendelsohn
Michael
M
D000595:Amino Acid Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D006801:Humans; D019913:Nuclear Localization Signals / Q000235:genetics; D015530:Nuclear Matrix / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic
C539127:NCOR1 protein, human; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha