T3 RECEPTORS IN GENE REGULATION AND ONCOGENESIS

甲状腺激素调节一个非常大的范围内的重要生物 包括发育、变态、生长、分化， 新陈代谢和体内平衡。一个核心问题是， 一系列程序可以由有限数量的激素调节， 个体反应可限于某些细胞类型， 发育阶段对这些机制的详细了解提供了 阐明生物程序和这些激素的最佳使用， 在治疗中的类似物。 与类固醇激素一样，甲状腺激素（T3）信号由 核受体属于最大的转录因子之一， 今天认识的家庭甲状腺激素反应的复杂性 在受体水平上由两个基因（TRalpha和TRalpha）在一定程度上显示， TRbeta）产生多种亚型，其中一些不是配体 依赖性转录激活因子。直到最近， TRs和类固醇激素受体一样， 涉及受体作为同源二聚体与受体结合的“直接”途径 特定的DNA序列。然而，在过去两年中，我们对如何 受体的运作方式发生了巨大的变化。最近的结果强烈 表明TRs需要与维甲酸X受体异二聚化 （RXRs）用于有效的DNA结合和功能。此外，TR已 发现通过一种新的“间接”机制调节基因转录， TR与转录因子AP-1相互作用。AP-1介导信号 通过生长因子、癌基因和肿瘤促进剂TPA的转导。通过 通过干扰该途径，TR可以起到抗癌基因的作用。 在未来的几年里，我们将进一步分析TR的基本机制 行动，以获得了解甲状腺激素的作用， 正常和疾病状态。我们将研究TR同源二聚体的作用 以及直接和间接反应途径中的异二聚体。的作用 TR羧基末端异构体的功能也将被分析 采用基因敲除技术并通过鉴定应答元件 和这些同种型的共受体。为了进一步了解TR如何 介导甲状腺激素和AP-1介导的信号传导之间的串扰， 分析TR-AP-1相互作用的分子机制的研究将是 贯彻这项研究将进一步加深我们对基因的理解。 由TRs控制的调节和途径。这些结果将提高我们的 了解T3在正常生理过程和疾病中的作用。

Thyroid hormones regulate a very large spectrum of important biological processes including development, metamorphosis, growth, differentiation, metabolism, and homeostasis. A central question has been how this large array of programs can be regulated by a limited number of hormones and how individual-responses can be restricted to certain cell types and developmental stages. A detailed understanding of these mechanisms offers elucidation of biological programs and optimal usage of these hormones and their analogs in therapies. Like the steroid hormones thyroid hormone (T3) signals are mediated by nuclear receptors that belong to one of the largest transcription factor families known today. The complexity of the thyroid hormone response is displayed to some degree at the receptor level by two genes (TRalpha and TRbeta) that give rise to multiple isoforms, some of which are not ligand dependent transcriptional activators. Until recently it had been assumed that TRs, like the steroid hormone receptors mainly function by one "direct" pathway that involves binding of the receptors as homodimers to specific DNA sequences. However, during the last two years our view on how the receptors operate has changed dramatically. Recent results strongly suggest that TRs require heterodimerization with Retinoid X Receptors (RXRs) for effective DNA binding and function. Furthermore, TRs have been found to regulate gene transcription by a novel "indirect" mechanism where TRs interact with the transcription factor AP-l. AP-l mediates signal transduction by growth factors, oncogenes, and the tumor promoter TPA. By interfering with this pathway, TRs can function as anti-oncogenes. In the coming years we will further analyze the basic mechanisms of TR action to obtain a basis for understanding thyroid hormone action in the normal and disease states. We will investigate the roles of TR homodimers and heterodimers in the direct and indirect response pathways. The role and function of TR carboxy terminal isoforms will also be analyzed employing gene knockout technology and by identifying response elements and co-receptors for these isoforms. To further understand on how TRs mediate crosstalk between thyroid hormones and AP- l mediated signalling, studies analyzing the molecular mechanism of TR-AP-1 interaction will be carried out. The proposed research will further our understanding of gene regulation and pathways controlled by TRs. These results will enhance our knowledge of T3 action in normal physiological processes and disease.