caa a22 4500 378861530 CHVBK 20180305123347.0 cr unu---uuuuu 161128e20030101xx s 000 0 eng 10.1351/pac200375111619 doi (NATIONALLICENCE)gruyter-10.1351/pac200375111619 Nuclear receptor superfamily: Principles of signaling [Elektronische Daten] [Pierre Germain, Lucia Altucci, William Bourguet, C. Rochette-Egly, Hinrich Gronemeyer] Nuclear receptors (NRs) comprise a family of 49 members that share a common structural organization and act as ligand-inducible transcription factors with major (patho)physiological impact. For some NRs ("orphan receptors”), cognate ligands have not yet been identified or may not exist. The principles of DNA recognition and ligand binding are well understood from both biochemical and crystal structure analyses. The 3D structures of several DNA-binding domains (DBDs),in complexes with a variety of cognate response elements, and multiple ligand-binding domains (LBDs), in the absence (apoLBD)and presence (holoLBD) of agonist, have been established and reveal canonical structural organization. Agonist binding induces a structural transition in the LBD whose most striking feature is the relocation of helix H12, which is required for establishing a coactivator complex, through interaction with members of the p160 family (SRC1, TIF2, AIB1) and/or the TRAP/DRIP complex. The p160-dependent coactivator complex is a multiprotein complex that comprises histone acetyltransferases (HATs), such as CBP,methyltransferases, such as CARM1, and other enzymes (SUMO ligase,etc.). The agonist-dependent recruitment of the HAT complex results in chromatin modification in the environment of the target gene promoters, which is requisite to, or may in some cases be sufficient for, transcription activation. In the absence of ligands, or in the presence of some antagonists, certain NRs are bound to distinct multiprotein complexes through the interaction with corepressors, such as NCoR and SMRT. Corepressor complexes comprise histone deacetylases (HDACs) that have the capacity to condense chromatin over target gene promoters. Ligands have been designed that selectively modulate the interaction between NRs and their coregulators. Both HATs and HDACs can also modify the acetylation status of nonhistone proteins, but the significance in the context of NR signaling is unclear. NRs communicate with other intracellular signaling pathways on a mutual basis, and their functionality may be altered, positively or negatively, by post-translational modification. The majority of NRs act as retinoid X receptor (RXR) heterodimers in which RXR cannot a priori respond autonomously to its cognate ligand to activate target gene transcription. This RXR subordination allows signaling pathway identity for the RXR partner. The corresponding mechanism is understood and reveals cell and NR selectivity, indicating that RXR can, under certain conditions, act autonomously. NRs are regulators of cell life and death,and NR malfunction can be at the basis of both disease and therapy, as is impressively documented in the case of acute promyelocytic leukemia. Recently, several pathways have been uncovered that link NR action with cell proliferation and apoptosis. © 2013 Walter de Gruyter GmbH, Berlin/Boston Germain Pierre IGBMC -B.P.10142, F-67404 Illkirch Cedex, C.U.de Strasbourg, France aut Altucci Lucia Dipartimento di Patologia Generale, Seconda Università di Napoli, Vico Luigi DeCrecchio 7, I-80138 Napoli, Italia aut Bourguet William CBS,CNRS U5048-INSERM U554,15 av.C. Flahault, F-34039 Montpellier, France aut Rochette-Egly C. IGBMC -B.P.10142, F-67404 Illkirch Cedex, C.U.de Strasbourg, France aut Gronemeyer Hinrich IGBMC -B.P.10142, F-67404 Illkirch Cedex, C.U.de Strasbourg, France aut Pure and Applied Chemistry De Gruyter 75/11-12(2003-01-01), 1619-1664 0033-4545 75:11-12<1619 2003 75 pac https://doi.org/10.1351/pac200375111619 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1351/pac200375111619 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Germain Pierre IGBMC -B.P.10142, F-67404 Illkirch Cedex, C.U.de Strasbourg, France aut NATIONALLICENCE 700 1- Altucci Lucia Dipartimento di Patologia Generale, Seconda Università di Napoli, Vico Luigi DeCrecchio 7, I-80138 Napoli, Italia aut NATIONALLICENCE 700 1- Bourguet William CBS,CNRS U5048-INSERM U554,15 av.C. Flahault, F-34039 Montpellier, France aut NATIONALLICENCE 700 1- Rochette-Egly C. IGBMC -B.P.10142, F-67404 Illkirch Cedex, C.U.de Strasbourg, France aut NATIONALLICENCE 700 1- Gronemeyer Hinrich IGBMC -B.P.10142, F-67404 Illkirch Cedex, C.U.de Strasbourg, France aut NATIONALLICENCE 773 0- Pure and Applied Chemistry De Gruyter 75/11-12(2003-01-01), 1619-1664 0033-4545 75:11-12<1619 2003 75 pac CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter