Genetic and Molecular Approaches to Signaling by Intracellular Receptors

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9604938 Yamamoto Technical Section There are five specific aims for this continuing investigation into the molecular mechanisms at several levels whereby signaling information is integrated by transcription regulators. 1. Extend the analysis of a specialized molecular chaperone complex, which includes Hsp90 and other components, to approach the mechanism by which it 'poises' the largest known class of regulators, the intracellular receptors (IRs)to be sensitive to their hormonal ligands, and to test the possibility that the chaperone complex is itself a signaling component that conveys information to aporeceptors; 2. Pursue findings that response elements, genomic sites to which IRs bind, confer signaling information that influences the mode of transcriptional regulation, e.g., activation or repression, that is imposed from the element; analyze both the signals intrinsic to the response elements and the sensing and interpretation mechanism within the receptors; 3. Carry out extensive analysis of the hormone binding domains of the glucocorticoid receptor (GR) and the thyroid receptor (TR), seeking common and unique features of their mechanisms; 4. Isolate and characterize a mammalian homolog of an ABC transporter first isolated in yeast that selectively exports certain steroids; seek other components that affect intracellular efficacy and potency of steroids, and ascertain whether such membrane components contribute to the cell specificity of hormone activity; 5. Investigate the functional consequences of GR phosphorylation, and test the possibility that recently detected interactions of GR and TR with cyclin-dependent kinase inhibitors termed INKs result in alterations of receptor and/or CDK activities and thereby comprise a signal integration circuit. Non-technical Section Genes in multicellular eukaryotes are subject to complex regulation, typically being regulated differentially in different cell types, developmental stages or physiological conditions. Understanding the mecha nisms of this complexity is an overarching problem in modern biology. It is apparent that many transcription regulators, factors that interact directly or indirectly with the RNA polymerization machinery, are at the distal end of signal transduction pathways that sense various biological signals and pass that information along a network.