Positive and Negative Regulation of Gene Transcription by GR. (A) Transrepression. Ligand-activated GR interacts with transcription factors like AP1 or NF-κβ by direct protein-protein contacts, thereby preventing them from binding to their cognate DNA sites and from activating the RNA polymerase II initiation complex. (B) nGREs. Negative regulation of gene transcription by ligand-activated GR in the POMC promoter involves binding of a GR trimer to a negative GRE (nGRE), thereby presumably intervening with upstream activating factors (X). Negative regulation at other nGREs, e.g., in the gene promoters of CRH, GnRH, prolactin, IL-1β, and osteocalcin involves the interplay with other transcription factors, e.g., AP-1, Pbx, and Oct-1. (C) Chromatin Remodeling. Coactivators of the p160 family such as SRC-1 (= NCoA-1), RAC3, GRIP1 (= TIF2 = NCoA-2), p/CIP (= ACTR), AIB1, and TRAM-1 bridge the DNA-bound GR dimer with a complex consisting of CBP or its homologue p300 and p/CAF. In addition, a ribonucleoprotein complex containing SRA (steroid receptor RNA activator) . RNA probably stabilizes the interaction of p160 proteins (e.g., SRC-1) with GR. Since the p160 family members, CBP/p300 and p/CAF all possess HAT (histone acetyl transferase) activity, this complex would result in remodeling the chromatin structure, thereby opening promoter regions. Moreover, CBP has the capability to directly bind to components of the basal transcription machinery. (D) Transactivation. DNA-bound GR dimer recruits the activation complex DRIP (probably identical to ARC and TRAP) which leads to activation of the RNA polymerase II complex. Mammalian homologues of the mediator/SRB proteins have been found both as components of the DRIP complex and associated with the CTD of RNA polymerase II, a functional interaction between these two protein complexes. Whether the chromatin remodeling complex (C) and the transactivating complex (D) function subsequently or concomitantly is not clear yet. Abbreviations: ACTR, activator of the thyroid and retinoic acid receptors; AIB1, amplified in breast cancer 1; ARC, activator-recruited cofactor; CBP, CRE binding protein; CRH, corticotropin-releasing hormone, DRIP, vitamin D receptor-interacting protein; GnRH, gonadotropin releasing hormone; GRE, glucocorticoid responsive element; GRIP1, glucocorticoid receptor interacting protein; HAT, histone acetyl transferase; Med, Mediator; NCoA, nuclear receptor coactivator; p/CAF, p300/CBP-associated factor; p/CIP, p300/CBP-co-integrator associated protein; POMC, pro-opiomelanocortin; RAC3, receptor-associated coactivator; SRA, steroid receptor RNA activator; SRC-1, steroid receptor coactivator 1; SRB, suppressor of RNA polymerase B mutations; TIF2, transcriptional intermediary factor; TRAM-1, Thyroid hormone receptor activator molecule 1; TRAP, thyroid receptor-associated protein.