In efforts to define mechanisms of transcriptional activation by the orphan nuclear receptor NGFI-B (Nur77), we identified TIF1 by mass spectrometry within a nuclear protein complex containing NGFI-B. TIF1, 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 Krü ppel-associated box domain-containing zinc finger transcription factors. TIF1 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 TIF1 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 TIF1 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 TIF1 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 TIF1 is recruited to the POMC promoter following CRH stimulation and that TIF1 potentiates CRH and protein kinase A signaling through the NurRE; it acts synergistically with the SRC2 coactivator. However, the actions of TIF1 and SRC2 were mapped to different NGFI-B AF-1 subdomains. Taken together, these results indicate that TIF1 is an important coactivator of NGFI-B-dependent transcription.
Few data have been collected on the use of debates as part of healthcare professional training. The impact of a debate on how pharmacy students feel about online pharmacy practice is described.
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