TIF1beta/KAP-1 is a coactivator of the orphan nuclear receptor NGFI-B/Nur77.
In efforts to define mechanisms of transcriptional activation by the orphan nuclear receptor NGFI-B (Nur77), we identified TIF1beta by mass spectrometry within a nuclear protein complex containing NGFI-B. TIF1beta, also known as KAP-1 (KRAB domain-associated protein) or KRIP-1, acts as a transcriptional corepressor for many transcription factors, in particular for ... the Krueppel-associated box domain-containing zinc finger transcription factors. TIF1beta is also an intrinsic component of two chromatin remodeling and histone deacetylase complexes, the N-CoR1 and nucleosome remodeling and deacetylation complexes. In contrast to these activities, we report that TIF1beta is a coactivator of NGFI-B and that it is as potent as the SRC coactivators in this context. Using pull-down assays and immunoprecipitation, we showed that TIF1beta interacts directly with NGFI-B and with other Nur family members. NGFI-B is an important mediator of hypothalamic corticotropin-releasing hormone (CRH) activation of proopiomelanocortin (POMC) transcription, and TIF1beta enhances transcription mediated through the NGFI-B target, the Nur response element (NurRE). The NurRE binds Nur factor dimers and is responsive to signaling pathways. In keeping with the role of NGFI-B as mediator of CRH signaling, we found that TIF1beta is recruited to the POMC promoter following CRH stimulation and that TIF1beta potentiates CRH and protein kinase A signaling through the NurRE; it acts synergistically with the SRC2 coactivator. However, the actions of TIF1beta and SRC2 were mapped to different NGFI-B AF-1 subdomains. Taken together, these results indicate that TIF1beta is an important coactivator of NGFI-B-dependent transcription.
Mesh Terms:
Cell Extracts, Cell Line, Cell Nucleus, Corticotropin-Releasing Hormone, Cyclic AMP-Dependent Protein Kinases, DNA-Binding Proteins, Humans, Molecular Weight, Nuclear Receptor Coactivator 2, Nuclear Receptor Subfamily 4, Group A, Member 1, Nuclear Receptor Subfamily 4, Group A, Member 2, Pro-Opiomelanocortin, Protein Binding, Protein Structure, Tertiary, Receptors, Steroid, Repressor Proteins, Response Elements, Signal Transduction, Transcription Factors, Transcription, Genetic
Cell Extracts, Cell Line, Cell Nucleus, Corticotropin-Releasing Hormone, Cyclic AMP-Dependent Protein Kinases, DNA-Binding Proteins, Humans, Molecular Weight, Nuclear Receptor Coactivator 2, Nuclear Receptor Subfamily 4, Group A, Member 1, Nuclear Receptor Subfamily 4, Group A, Member 2, Pro-Opiomelanocortin, Protein Binding, Protein Structure, Tertiary, Receptors, Steroid, Repressor Proteins, Response Elements, Signal Transduction, Transcription Factors, Transcription, Genetic
J. Biol. Chem.
Date: May. 22, 2009
PubMed ID: 19321449
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