Genetic and Molecular Approaches to Signaling by Intracellular Receptors

小行星9604938 技术部分在转录调节因子整合信号信息的几个水平上，对分子机制的持续研究有五个具体目标。 1.扩展一个专门的分子伴侣复合物，其中包括热休克蛋白90和其他组件的分析，以接近的机制，它'poises'最大的已知类别的监管机构，细胞内受体（IR）是敏感的激素配体，并测试的可能性，伴侣复合物本身是一个信号传导组件，传递信息的aporeceptors; 2。追求的结果，反应元件，IR结合的基因组位点，赋予信号传导信息，影响转录调控的模式，例如，激活或抑制，这是强加的元素;分析信号固有的响应元件和传感器内的传感和解释机制; 3.对糖皮质激素受体（GR）和甲状腺受体（TR）的激素结合结构域进行广泛分析，寻求其机制的共同和独特特征; 4.分离和表征首先在酵母中分离的ABC转运蛋白的哺乳动物同系物，其选择性地输出某些类固醇;寻找影响类固醇的细胞内功效和效力的其他组分，并确定这些膜组分是否有助于激素活性的细胞特异性; 5.研究GR磷酸化的功能后果，并测试最近检测到的GR和TR与称为INKs的细胞周期蛋白依赖性激酶抑制剂的相互作用导致受体和/或CDK活性改变的可能性，从而构成信号整合电路。 多细胞真核生物中的基因受到复杂的调控，通常在不同的细胞类型、发育阶段或生理条件下受到差异性的调控。理解这种复杂性的机制是现代生物学的首要问题。很明显，许多转录调节因子，即直接或间接与RNA聚合机制相互作用的因子，位于信号转导途径的远端，这些信号转导途径感知各种生物信号并将该信息沿着网络传递。

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.