CELL ADHESION AND APOPTOSIS

大多数人类癌症起源于上皮细胞。许多癌细胞都有 在培养中接近正常的形态和生长速度，表明 他们的主要缺陷是未能对不明身份的 活体内的细胞凋亡挑战。最近，我报道说， 上皮整合素介导的细胞-基质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 致失巢细胞实际上是由癌基因减少，而由肿瘤增加。 抑制基因，表明基因可能通过以下途径促进癌症 控制阿尼基。 该项目将测试整合素和整合素相关信号的作用 控制失眠的传感器。 具体地说，整合素β亚单位胞浆结构域的作用， 已知启动整合素信号的某些方面，将是 测试过。这些由多个基因产生的结构域也因此而不同 选择性剪接和磷酸化。整合素表达异常 常见于肿瘤细胞。通过表达异常整合素类型， 肿瘤细胞可能能够逃脱失巢凋亡。这一假设将得到检验。 通过比较不同的β亚单位胞质结构域 聚集后，将细胞从失巢失巢中拯救出来的能力。 其他研究人员已经确立了焦点粘连的核心作用 激酶(FAK)在整合素信号传导中的作用。FAK的一种激活形式最近是 发现可以从失巢失巢中拯救上皮细胞(初步研究)。这个 FAK在失巢失巢中的作用将通过使用特定的 突变影响其信号和细胞骨架的各个方面 联想。 一些报告已经指出了ras或ras样G- 蛋白质，Rho，整合素信号。这些分子的功能和 将分两个阶段检查它们在失巢蛋白中的下游效应器。 首先，将检测它们通过黏附激活的情况。其次，我们将 测试表达突变激活形式对失巢凋亡的影响。 某些激活的信号分子可能参与上皮细胞 转变主要是通过减轻失巢障碍。这个项目已经 确认FAK就是这样的一个分子。其他人的身份识别将 阐明控制失巢的途径，加强我们的理解 上皮性癌变的可能性。

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.