Regulation of TGF-beta Signaling in the Prostate

前列腺中 TGF-β 信号传导的调节

• 批准号: 6613608
• 负责人: DAVID DANIELPOUR
• 金额: $ 24.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613608
• 关键词: AP1 protein; apoptosis; biological signal transduction; cell line; epidermal growth factor; gene induction /repression; growth factor receptors; microarray technology; mitogen activated protein kinase; neoplasm /cancer genetics; neoplastic process; northern blottings; prostate; protein structure function; receptor expression; regulatory gene; transforming growth factors; tumor suppressor proteins

DESCRIPTION (revised by applicant): In the prostate, transforming growth factor-beta (TGFb) promotes growth arrest and apoptosis of epithelial cells and can either suppress or promotes tumor growth. The mechanisms by which TGFb mediates these processes are under intense investigation. TGFbl signals through promoting the binding and activation of the TGFb type I receptor (TbRI) by TbRII. Activated TbRI phosphorylates Smads 2 and 3, which promotes both their and Smad4's entry in the nucleus, where they directly or indirectly regulate transcription. A current dogma in this field is that TbRII signals only through activation of TbRI. Another dogma is that Smads are the critical trigger of virtually all TGF-b responses including growth arrest and apoptosis. However, accumulating evidence is strengthening the notion that TGFb activates a number of other kinases (i.e., MAPKs) independent of Smads. Despite these advances, nothing is known about how TbRI and TbRII activate such Smad-independent signal. We propose to test the following hypothesis: TbRII is critical to TGFb signal transduction not only through activating TbRI, that activates receptor Smads, but also by mediation of Smad-independent TGFb signals. We will test this hypothesis in prostatic epithelial cell lines by studying: i) the role of EGF in regulating TGFb responses, ii) the structural/functional basis of TbRI and TbRII and the role of Smads and MAPKs in the activation of AP-1, and iii) regulation of growth inhibition by constitutively activated Smads.

描述（由申请人修订）：在前列腺中，转化生长因子-β（TGF β）促进上皮细胞的生长停滞和凋亡，并可抑制或促进肿瘤生长。TGF β介导这些过程的机制正在深入研究中。TGF β 1通过促进TGF β I型受体（TbRI）与TbRII的结合和活化而发出信号。活化的TbRI磷酸化Smads 2和3，这促进它们和Smad4进入细胞核，在那里它们直接或间接地调节转录。该领域中的当前教条是TbRII仅通过TbRI的激活来发信号。另一个教条是Smads是几乎所有TGF-β反应的关键触发剂，包括生长停滞和凋亡。然而，越来越多的证据正在加强TGF β激活许多其他激酶（即，MAPKs）独立于Smads。尽管取得了这些进展，但TbRI和TbRII如何激活这种Smad非依赖性信号尚不清楚。我们提出测试以下假设：TbRII是至关重要的TGF β信号转导不仅通过激活TbRI，激活受体Smads，但也通过介导的Smad非依赖性TGF β信号。我们将在前列腺上皮细胞系中通过以下研究来检验这一假设：i）EGF在调节TGF β反应中的作用，ii）TbRI和TbRII的结构/功能基础以及Smads和MAPK在AP-1活化中的作用，以及iii）组成性活化Smads对生长抑制的调节。