Nuclear receptors, their coactivators and modulation of transcription.

Nuclear receptors are ligand-dependent transcription factors which can also be activated in the absence of their lipophilic ligands by signaling substances acting on cell membrane receptors. This ligand-independent activation indicates the importance of nuclear receptor phosphorylation for their function. Nuclear receptor-mediated transcription of target genes is further increased by interactions with recruited coactivators forming a novel family of nuclear proteins. CBP/p300, a coactivator of different classes of transcription factors, including the tumor suppressor protein p53, plays a special role acting as a bridging protein between inducible transcription factors and the basal transcription apparatus, and as an integrator of diverse signaling pathways. Coactivators of nuclear receptors and associated proteins forming a multicomponent complex have an intrinsic histone acetylase activity in contrast to nuclear receptor and heterodimer Mad-Max corepressors, which recruit histone deacetylase. Similarly the Rb protein interacts with histone deacetylase to repress transcription of cell cycle regulatory genes. Targeted histone acetylation/deacetylation results in remodeling of chromatin structure and correlates with activation/repression of transcription. Recent data point to the important role of coactivator proteins associated with inducible transcription factors in transcription regulation, and in the integration of multiple signal transduction pathways within the nucleus.