MECHANISMS OF RAS MEDIATED INDEPENDENCE FROM ADHESION

RAS 介导的粘附独立性机制

• 批准号: 6377728
• 负责人: AIDAN J MCFALL
• 金额: $ 3.43万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6377728
• 关键词: JUN kinase; apoptosis; autocrine; cell adhesion; cell line; colon neoplasms; enzyme activity; epidermal growth factor; epithelium; growth factor receptors; guanine nucleotide binding protein; mutant; nuclear factor kappa beta; oncoproteins; phosphatidylinositol 3 kinase; transforming growth factors

Activation of the Ras protein contributes to the development of a wide variety of human cancers. In addition to its growth-promoting properties Ras has recently been identified as a potent inhibitor of anoikis, or suspension-induced cell death. Anoikis represents a physiologically appropriate response of epithelial cells to loss of adhesion. Circumventing this response is a prerequisite for metastasis, one of the most lethal aspects of cancer. The work proposed in this fellowship utilizes a novel model for anoikis studies, the Rat Intestinal Epithelial-1 (RIE-1) cell line, to identify signaling properties of Ras that block anoikis. Unlike what has been proposed with other epithelial cell lines, preliminary data suggest that multiple signaling properties of Ras promote anoikis resistance of RIE-1 cells. The specific aims of this research are to determine (i) what effector(s) of Ras contributes to anoikis resistance, (ii) the role of a Ras/Epidermal Growth Factor Receptor autocrine loop in mediating anoikis resistance, (iii) if Ras-mediated regulation of the Jun terminal Kinase or Nuclear Factor kappa B activity attenuates anoikis and (iv) if loss of mutant Ras expression or inactivation of Ras effectors can restore anoikis sensitivity to the human colon carcinoma cell line DLD-1.

RAS蛋白的激活有助于多种人类癌症的发展。 除了其生长促进特性外，RAS最近被确定为厌氧菌的有效抑制剂，或悬浮诱导的细胞死亡。 Anoikis代表上皮细胞对粘附丧失的生理适当反应。 规避这种反应是转移的先决条件，这是癌症最致命的方面之一。该研究金提出的工作利用了一种新型模型，用于厌氧研究，即大鼠肠上皮-1（RIE-1）细胞系，以识别阻断Anoikis的Ras的信号传导性能。与其他上皮细胞系提出的不同，初步数据表明，RAS的多个信号传导特性促进了RIE-1细胞的抗Anoikis耐药性。 The specific aims of this research are to determine (i) what effector(s) of Ras contributes to anoikis resistance, (ii) the role of a Ras/Epidermal Growth Factor Receptor autocrine loop in mediating anoikis resistance, (iii) if Ras-mediated regulation of the Jun terminal Kinase or Nuclear Factor kappa B activity attenuates anoikis and (iv) if loss of mutant Ras expression or RAS效应子的失活可以恢复对人结肠癌细胞系DLD-1的敏感性。