TIF1β/KAP-1 Is a Coactivator of the Orphan Nuclear Receptor NGFI-B/Nur77

Abstract

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.

A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation

“…These results established KAP1 as a coactivator of MyoD/ Mef2D-dependent gene expression, reminiscent of its previously reported stimulation of Nur77 transcriptional activating potential (Rambaud et al 2009). However, the association of KAP1 with MyoD and Mef2D in both Figure 2.…”

Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

“…4). NR4A proteins have previously been shown to interact with other proteins implicated in DNA repair (Galleguillos et al 2004;Ohkura et al 2008;Rambaud et al 2009). Thus, the corresponding mRNAs (and the mRNA encoding the Ku80 subunit of DNA-PK) were down-regulated by siRNA transfection in U2OS cells, followed by exposure to IR and analysis of NR4A cellular distribution.…”

Are corepressors always repressors?

“…For example, the coactivator KAP-1 (also known as TIF1b or TRIM28) can also function as a corepressor, 26 suggesting that the classification of cofactors as corepressors or coactivators cannot be considered too rigidly. …”