Regulation of TGF-beta Signaling in the Prostate

描述（由申请人修改）：在前列腺中，转化生长因子- β (TGFb)促进上皮细胞的生长阻滞和凋亡，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。TGFbl信号通过TbRII促进TGFb I型受体（TbRI）的结合和激活。激活的TbRI磷酸化smad2和3，促进它们和Smad4进入细胞核，在那里它们直接或间接调节转录。目前该领域的一个教条是，TbRI仅通过激活TbRI来发出信号。另一个教条是Smads是几乎所有TGF-b反应的关键触发因素，包括生长停滞和细胞凋亡。然而，越来越多的证据正在加强TGFb激活一些独立于Smads的其他激酶（即MAPKs）的观点。尽管取得了这些进展，但对于TbRI和TbRII如何激活这种与smad无关的信号，我们一无所知。我们提出验证以下假设：TbRII不仅通过激活激活受体Smads的TbRI，而且通过介导smad无关的TGFb信号对TGFb信号转导至关重要。我们将在前列腺上皮细胞系中验证这一假设，通过研究：i) EGF在调节TGFb应答中的作用，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.