Regulation of TGF-beta Signaling in the Prostate

前列腺中 TGF-β 信号传导的调节

• 批准号: 7048628
• 负责人: DAVID DANIELPOUR
• 金额: $ 24.51万
• 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/7048628
• 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（申请人修订）：在前列腺中，转化生长因子-β（TGFb）促进上皮细胞的生长停滞和凋亡，并且可以抑制或促进肿瘤生长。 TGFb 介导这些过程的机制正在深入研究中。 TGFb1通过TbRII促进TGFb I型受体(TbRI)的结合和激活来发出信号。激活的 TbRI 磷酸化 Smads 2 和 3，从而促进它们和 Smad4 进入细胞核，直接或间接调节转录。该领域目前的一个教条是 TbRII 信号只能通过 TbRI 的激活来发出。另一个教条是，Smads 是几乎所有 TGF-b 反应（包括生长停滞和细胞凋亡）的关键触发因素。然而，越来越多的证据正在强化这样的观点：TGFb 可以独立于 Smad 激活许多其他激酶（即 MAPK）。尽管取得了这些进展，但关于 TbRI 和 TbRII 如何激活这种不依赖于 Smad 的信号仍一无所知。我们建议检验以下假设：TbRII 对 TGFb 信号转导至关重要，不仅通过激活 TbRI（激活受体 Smads），而且还通过介导不依赖于 Smad 的 TGFb 信号。我们将通过研究以下内容在前列腺上皮细胞系中检验这一假设：i) EGF 在调节 TGFb 反应中的作用，ii) TbRI 和 TbRII 的结构/功能基础以及 Smads 和 MAPKs 在 AP-1 激活中的作用，以及 iii) 组成型激活的 Smads 对生长抑制的调节。