Role of the Type III TGF-Beta Receptor in Cancer Biology

III 型 TGF-β 受体在癌症生物学中的作用

• 批准号: 6886774
• 负责人: GERARD C BLOBE
• 金额: $ 24.57万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6886774
• 关键词: athymic mouse; biological signal transduction; breast neoplasms; carcinogenesis; cell line; enzyme activity; female; growth factor receptors; growth inhibitors; human tissue; immunocytochemistry; neoplastic growth; pathologic process; proteasome; protein binding; protein structure function; receptor expression; tissue /cell culture; transforming growth factors; tumor suppressor proteins; ubiquitin; western blottings

DESCRIPTION (provided by applicant): Transforming growth factor-beta (TGF-beta) is a potent inhibitor of human mammary epithelial proliferation; during mammary carcinogenesis most breast cancers become resistant to TGF-beta while retaining expression of the core members of the TGF-a signaling pathway (the type I and II TGF-beta receptors, Smads 2, 3 and 4) Thus a fundamental gap in knowledge exists in terms of the mechanism by which breast cancers become resistant to TGF-beta. The type III TGF-beta receptor (TbetaRIII) has an emerging yet poorly understood role it regulating TGF-beta signaling. Based on preliminary studies the following hypothesis is proposed: Decreased TbetaRIII expression at the protein level mediated through decreased expression of the TbetaRIII stabilizing protein, GIPC, and/or by increased degradation by the ubiquitin/proteasome pathway confers resistance to TGF-beta-mediated inhibition of proliferation and defines TbetaRIII as a tumor suppressor in breast cancer. This hypothesis will be addressed by, four Specific Aims. Specific Aim 1: The effect of GIPC expression on TbetaRIII TbetaRIII functions will be established to define the mechanism by which GIPC-mediated decreases in TbetaRIII expression confers resistance to TGF-beta-mediated inhibition of proliferation in human breast cancer cells. Specific Aim 2: The site of TbetaRIII ubiquitination and effect of the ubiquitin/proteasome pathway on TbetaRIII functions will be established to define the mechanism by which ubiquitin/proteasome-mediated decreases in TbetaRIII expression confers resistance to TGF-beta-mediated inhibition of proliferation in human breast cancer cells. Specific Aim 3: The effect of altering TbetaRIII expression (through GIPC and the ubiquitin/proteasome pathway) on the tumorigenicity of human breast cancer cells will be established to define whether TbetaRIII functions as a tumor suppressor in breast cancer cells. Specific Aim 4: The expression of TbetaRIII, GIPC, ubiquitinated TbetaRIII and the E2/E3 enzymes which ubiquitinate TbetaRIII at the protein level will be established to determine whether TbetaRIII expression is decreased by GIPC or the ubiquitin/proteasome pathway in human breast cancers. These studies will determine whether TbetaRIII functions as a tumor suppressor in breast cancer, define mechanisms for its regulated expression and aid in the design of interventions to manipulate TaRIII and the TGF-beta signaling pathway for the chemoprevention and treatment of breast cancer.

描述（由申请人提供）：转化生长因子-β（TGF-β）是人类乳腺上皮增殖的有效抑制剂；在乳腺癌发生过程中，大多数乳腺癌对 TGF-β 产生耐药性，同时保留 TGF-α 信号通路核心成员（I 型和 II 型 TGF-β 受体，Smads 2、3 和 4）的表达，因此存在根本性的知识空白存在于乳腺癌对 TGF-β 产生耐药性的机制方面。 III 型 TGF-β 受体 (TbetaRIII) 在调节 TGF-β 信号传导方面发挥着新兴但尚不清楚的作用。根据初步研究，提出以下假设：通过 TbetaRIII 稳定蛋白 GIPC 表达减少和/或泛素/蛋白酶体途径降解增加介导的蛋白质水平 TbetaRIII 表达减少，赋予对 TGF-β 介导的抑制的抗性增殖并将 TbetaRIII 定义为乳腺癌的肿瘤抑制因子。这一假设将通过四个具体目标来解决。具体目标 1： GIPC 表达对 TbetaRIII 功能的影响将被建立，以定义 GIPC 介导的 TbetaRIII 表达减少赋予人乳腺癌细胞对 TGF-β 介导的增殖抑制的抗性的机制。具体目标 2：将建立 TbetaRIII 泛素化位点以及泛素/蛋白酶体途径对 TbetaRIII 功能的影响，以定义泛素/蛋白酶体介导的 TbetaRIII 表达降低对 TGF-β 介导的增殖抑制产生抗性的机制。人类乳腺癌细胞。具体目标 3：将确定改变 TbetaRIII 表达（通过 GIPC 和泛素/蛋白酶体途径）对人乳腺癌细胞致瘤性的影响，以确定 TbetaRIII 是否在乳腺癌细胞中发挥肿瘤抑制因子的作用。具体目标 4：建立 TbetaRIII、GIPC、泛素化 TbetaRIII 和在蛋白质水平上泛素化 TbetaRIII 的 E2/E3 酶的表达，以确定人乳腺癌中 GIPC 或泛素/蛋白酶体途径是否会降低 TbetaRIII 表达。这些研究将确定 TbetaRIII 是否在乳腺癌中发挥肿瘤抑制因子的作用，定义其调节表达的机制，并帮助设计干预措施来操纵 TaRIII 和 TGF-β 信号通路，以进行乳腺癌的化学预防和治疗。