CELL ADHESION AND APOPTOSIS

细胞粘附和凋亡

• 批准号: 2685039
• 负责人: Steven Miles Frisch
• 金额: $ 26.65万
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2685039
• 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.

大多数人类癌症起源于上皮细胞。许多癌细胞具有 在培养物中几乎正常的形态和生长速率，这表明， 他们的主要缺陷是未能对一个身份不明的 体内凋亡攻击。最近，我报道说， 上皮整合素介导的细胞-基质相互作用引起细胞凋亡 （称为“失巢”）。我进一步证明了细胞的敏感性 事实上，癌基因减少了失巢凋亡，肿瘤增加了失巢凋亡。 抑制基因，表明基因可能有助于癌症， 控制失巢凋亡 本项目将测试整合素的作用及整合素相关信号 控制失巢凋亡的传感器。 具体而言，整联蛋白β亚基胞质结构域的作用， 已知它们会启动整合素信号传导的某些方面， 测试.这些结构域由多个基因产生， 选择性剪接和磷酸化。整合素异常表达 在肿瘤细胞中很常见。通过表达异常整合素类型， 肿瘤细胞可能能够逃避失巢凋亡。这一假设将得到检验 通过比较各种β亚基胞质结构域， 聚类后，从失巢凋亡中拯救细胞的能力。 其他研究者已经确立了局灶性粘连的核心作用 整合素信号传导中的激酶（FAK）。一种激活形式的FAK最近被 发现可从失巢凋亡中拯救上皮细胞（初步研究）。的 FAK在失巢凋亡中的作用将通过使用特定的 影响其信号传导和细胞骨架的各个方面的突变 协会. 一些报告指出ras或ras样G- 蛋白质rho在整合素信号传导中的作用。 这些分子的功能和 将分两个阶段研究失巢凋亡中的下游效应物。 首先，将测定它们通过粘附的活化。其次，我们将 测试表达突变激活形式对失巢凋亡的影响。 某些激活信号分子可能有助于上皮细胞 主要通过减轻失巢凋亡来转化。该项目已经 发现FAK就是这样一种分子。其他人的身份将 阐明控制失巢凋亡的途径，加强我们对 上皮细胞癌变的过程