Role of cofactors in nuclear hormone receptor function.

核受体是激素调节的转录因子，控制正常后生动物繁殖、分化和体内平衡的许多关键方面；核受体异常是多种人类内分泌和肿瘤疾病的病因。本研究的最终目标是更好地了解核受体如何参与正常细胞的信号转导，以及在这一过程中导致疾病的病变。许多核受体表现出双峰转录特性，可以抑制或激活基因表达。我们和其他人已经确定了一个“辅抑制因子”家族，它与核受体物理关联，募集额外的蛋白质，并介导转录抑制。许多影响核受体功能的信号通过改变辅抑制子的募集或功能来表现其作用。我们建议继续研究核受体的作用是如何通过这些辅抑制因子介导的。虽然这些研究的重点是抑制，但这些研究的各个方面也将涉及共激活物的功能，以及核受体功能的其他效应物和调节剂。我们的实验将解决五个广泛问题的具体方面：为什么不同的核受体同工异构体与辅抑制子相互作用和介导抑制的能力不同？具体目标2。目标DNA的性质如何影响抑制？具体目标3。不同激素配体的结合是如何调节抑制的？具体目标非配体信号转导通路如何调节抑制？5.具体目标协同抑制因子功能缺陷是如何导致疾病的？这些实验的结果将有助于更好地理解核激素受体在正常和患病生物体中的功能背后的分子基础。更广泛。，我们预计，我们的研究辅抑制作用将有助于澄清真核生物转录抑制的更普遍的现象。

Nuclear receptors are hormone-regulated transcription factors that control many key aspects of normal metazoan reproduction, differentiation, and homeostasis; aberrant nuclear receptors are causal factors in a variety of human endocrine and neoplastic disorders. The ultimate goal of this proposal is to better understand how nuclear receptors participate in signal transduction in normal cells, and the lesions in this process that lead to disease. Many nuclear receptors exhibit bimodal transcriptional properties, and can either repress or activate gene expression. We and others have identified a family of "corepressors" that physically associate with nuclear receptors, recruit additional proteins, and mediate transcriptional repression. Many signals that impact on nuclear receptor function manifest their effects through changes in corepressor recruitment or function. We propose to continue our research into how the actions of nuclear receptors are mediated through these corepressors. Although focused on repression, aspects of these studies will also touch on the functions of coactivators, and on additional effectors and regulators of nuclear receptor function. Our experiments will address specific aspects of five broad questions: Specific Aim 1. Why do different nuclear receptor isoforms differ in the ability to interact with corepressor and mediate repression? Specific Aim 2. How does the nature of target DNA influence repression? Specific Aim 3. How does the binding of different hormone ligands regulate repression? Specific Aim 4. How do non-ligand signal transduction pathways regulate repression? Specific Aim 5. How do defects in corepressor function lead to disease? The results from these experiments will contribute to a better understanding of the molecular basis behind nuclear hormone receptor function in both the normal and diseased organism. More broadly., we anticipate that our studies of corepressor action will help clarify the more general phenomenon of eukaryotic transcriptional repression.