Regulation of Gut Epithelial Cell Proliferation

描述（由申请人提供）：越来越多的证据表明， 肽的转化生长因子-β（TGF-β）家族具有关键的 在胃肠道中起作用。在正常上皮细胞中，包括 在肠上皮中，TGF-β具有主要的生长抑制作用， 起到肿瘤抑制作用。肿瘤性转化导致 这种正常的生长抑制反应TGF-β失活突变 受体和选择的TGF-β信号转导蛋白（Smad家族 蛋白质）与人类结肠直肠癌的显著部分相关， 和胰腺癌另一方面，在选定的条件下， 可能会促进肿瘤的发生。有几条证据表明， 对TGF-β的反应可能主要是促进肿瘤的， 无论是长期暴露于高水平的TGF-β细胞或后， 致癌转化根据这些观察，我们开发了 以下中心假设：TGF-β覆盖的肿瘤促进作用 在肠和其他类型的转化过程中的肿瘤抑制作用 上皮细胞，由于TGF-β信号转导的开关。尽管损失 生长抑制信号，肿瘤促进信号通过TGF-β 受体保持完整。从中心假设中产生的次要假设 将在以下具体目标下检验这一假设。具体目标1： 确定肠上皮细胞中TGF-β信号改变的机制 表达ras癌基因的细胞。根据目标1，我们将确定以下机制： Smad 4下调Ras转化的条件下，我们将 从我们的研究中确定这一新观察的生物学意义。 初步研究。具体目标2：确定Smad和 TGF-β促肿瘤作用中的Smad非依赖性信号转导 肠上皮细胞在这个具体目标中，我们将确定 TGF-β肿瘤促进中的Smad和Smad非依赖性信号通路。 具体目标3：确定E-钙粘蛋白下调在肿瘤细胞凋亡中的作用。 由致癌Ras和TGF-β诱导的侵袭性表型。在这一目标下，我们 将决定羽绒的机制和生物学重要性 Ras和TGF-β对肿瘤形成的E-钙粘蛋白的调节， 侵略性一个长期目标是确定新的治疗策略， 选择性靶向TGF-β的肿瘤促进作用，同时保留 肿瘤抑制作用。

DESCRIPTION (provided by applicant): There is a growing body of evidence that the Transforming growth factor-beta (TGF-beta) family of peptides has critical functions in the gastrointestinal tract. In normal epithelial cells, including intestinal epithelium, TGF-beta has a predominant growth-inhibitory effect and serves a tumor suppressor role. Neoplastic transformation results in loss of this normal growth-inhibitory response. Inactivating mutations of TGF-beta receptors and selected TGF-beta signal transduction proteins (Smad family proteins) have been associated with a significant fraction of human colorectal and pancreatic cancers. On the other hand, under selected conditions TGF-beta may actually promote tumorigenesis. Several lines of evidence reveal that the responses to TGF-beta may become predominantly tumor-promoting in the context of either prolonged exposure of cells to high levels of TGF-beta or after oncogenic transformation. Based on these observations, we have developed the following central hypothesis: Tumor promoting effects of TGF-beta override tumor suppressor effects during transformation of intestinal and other types of epithelial cells, due to a switch in TGF-beta signal transduction. Despite loss of growth inhibitory signaling, the tumor promoting signaling via the TGF-beta receptors remains intact. Secondary hypotheses that emanate from the central hypothesis will be tested under the following specific aims. Specific Aim 1: To determine the mechanism of altered TGF-beta signaling in intestinal epithelial cells expressing ras oncogenes. Under Aim 1 we will determine the mechanism for Smad4 down regulation under conditions of Ras transformation and we will determine the biological significance of this novel observation from our preliminary studies. Specific Aim 2: To determine the roles of Smad and Smad-independent signal transduction in tumor-promoting effects of TGF-beta in intestinal epithelial cells. In this Specific Aim we will determine the role of both Smad and Smad-independent signaling pathways in TGF-beta tumor promotion. Specific Aim 3: To determine the role of E-cadherin down regulation in the invasive phenotype induced by oncogenic Ras and TGF-beta. Under this aim, we will determine the mechanism and the biological importance of the down regulation of E-cadherin by Ras and TGF-beta for tumor formation and invasiveness. A long-term goal is to identify novel therapeutic strategies that selectively target the tumor promoting effects of TGF-beta, while preserving the tumor-suppressive actions.