CELL ADHESION AND APOPTOSIS

细胞粘附和凋亡

• 批准号: 2900820
• 负责人: Steven Miles Frisch
• 金额: $ 27.72万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900820
• 关键词: G protein; apoptosis; biological signal transduction; cell adhesion; epithelium; immunoprecipitation; integrins; oncogenes; protein structure function; protein tyrosine kinase; tissue /cell culture; tumor suppressor genes; western blottings

Most human cancers arise from epithelial cells. Many carcinoma cells have nearly normal morphologies and growth rates in culture, suggesting that their primary defect is in their failure to respond to an unidentified apoptotic challenge in vivo. Recently, I reported that the disruption of epithelial integrin-mediated cell-matrix interactions causes apoptosis (termed "anoikis"). I further demonstrated that the sensitivity of cells to anoikis was in fact reduced by oncogenes and increased by tumor suppressor genes, demonstrating that genes may contribute to cancer by controlling anoikis. This project will test the role of integrins and integrin-related signal transducers in the control of anoikis. Specifically, the role of the integrin beta subunit cytoplasmic domains, which are known to initiate some aspects of integrin signaling, will be tested. These domains, arising from multiple genes, also vary as a result of alternative splicing and phosphorylation. Anomalous integrin expression is often seen in tumor cells. By expressing anomalous integrin types, tumor cells may be able to escape anoikis. This hypothesis will be tested by comparing the various beta subunit cytoplasmic domains for their ability, after clustering, to rescue cells from anoikis. Other investigators have established a central role for Focal Adhesion Kinase (FAK) in integrin signaling. An activated form of FAK was recently found to rescue epithelial cells from anoikis (Preliminary Studies). The role of FAK in anoikis will be investigated further by the use of specific mutations affecting various aspects of its signaling and cytoskeletal associations. Several reports have indicated the importance of ras or the ras-like G- protein, rho, in integrin signaling. The function of these molecules and their downstream effectors in anoikis will be examined in two stages. First, their activation by adhesion will be assayed. Secondly, we will test the effects of expressing mutationally activated forms on anoikis. Certain activating signaling molecules may contribute to epithelial transformation primarily by alleviating anoikis. This project has already identified FAK as one such molecule. The identification of others will elucidate a pathway that controls anoikis, strengthening our understanding of epithelial carcinogenesis.

大多数人类癌症来自上皮细胞。许多癌细胞具有 文化中几乎正常的形态和增长率，表明 他们的主要缺陷是他们未能对身份不明的响应 体内凋亡挑战。最近，我报道了 上皮整联蛋白介导的细胞玛尔trix相互作用导致细胞凋亡 （称为“ Anoikis”）。我进一步证明了细胞的敏感性 实际上，癌基因降低了Anoikis，肿瘤增加了 抑制基因，证明基因可能会导致癌症 控制Anoikis。 该项目将测试整联蛋白和整合素相关信号的作用 控制ANOIKIS的传感器。 具体而言，整联蛋白β亚基细胞质结构域的作用， 已知会启动整联蛋白信号传导的某些方面，将是 测试。这些域是由多个基因引起的，结果也有所不同 替代剪接和磷酸化。异源整合素表达 通常在肿瘤细胞中看到。通过表达异常整联蛋白类型， 肿瘤细胞可能能够逃脱Anoikis。该假设将进行检验 通过比较各种β亚基细胞质结构域 聚类后​​的能力从Anoikis救出细胞。 其他研究人员已经确立了焦点粘附的核心作用 整联蛋白信号传导中的激酶（FAK）。最近是一种激活的FAK形式 发现可以从Anoikis中挽救上皮细胞（初步研究）。这 FAK在Anoikis中的作用将通过特定的使用进一步研究 影响其信号传导和细胞骨架的各个方面的突变 协会。 几份报告表明RAS或类似RAS的G-的重要性 蛋白质，Rho，在整联蛋白信号传导中。 这些分子的功能和 它们在Anoikis中的下游效应子将在两个阶段进行检查。 首先，将测定它们通过粘附的激活。其次，我们会的 测试表达突变激活形式对Anoikis的影响。 某些激活信号分子可能有助于上皮 转型主要是通过减轻Anoikis。这个项目已经 将FAK确定为这样的分子。他人的识别将 阐明控制Anoikis的途径，增强我们的理解 上皮癌变。