Regulation of TGF-beta Signaling in the Prostate

描述(申请人审校)：在前列腺，转化生长因子-β(TGFb)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。TGFb介导这些过程的机制正在深入研究中。TGFb1通过促进TbRII与TGFbI型受体(TGFbI型受体)的结合和激活来传递信号。激活的TbRI使Smad2和Smad3磷酸化，从而促进它们和Smad4‘S进入细胞核，在那里它们直接或间接地调节转录。该领域目前的一种信条是，TbRII仅通过激活TbRI来发出信号。另一个教条是，Smads是几乎所有转化生长因子-b反应的关键触发因素，包括生长停滞和细胞凋亡。然而，越来越多的证据强化了这样的观点，即TGFb激活了许多不依赖Smads的其他激酶(即MAPK)。尽管取得了这些进展，但关于TbRI和TbRII是如何激活这种Smad非依赖性信号的尚不清楚。我们建议验证以下假设：TbRII不仅通过激活TbRI激活受体Smads，而且通过介导Smad非依赖性TGFb信号对TGFb信号转导起关键作用。我们将通过以下研究在前列腺上皮细胞系中验证这一假说：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)结构性激活的Smads对生长抑制的调节。

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.