Role of Protein Kinase C Iota in Colon Carcinogenesis

蛋白激酶 C Iota 在结肠癌发生中的作用

• 批准号: 7049701
• 负责人: Nicole R Murray
• 金额: $ 6.9万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049701
• 关键词: apoptosis; carcinogenesis; cell differentiation; cell proliferation; colon; colon neoplasms; dietary lipid; enzyme activity; enzyme induction /repression; gastrointestinal epithelium; genetically modified animals; guanine nucleotide binding protein; laboratory mouse; nuclear factor kappa beta; nutrition related neoplasm /cancer; nutrition related tag; omega 3 fatty acid; oncoproteins; polymerase chain reaction; protein kinase C; unsaturated fatty acids; vegetable oils

DESCRIPTION (provided by applicant): Colon cancer results from progressive disregulation of the normal growth inhibitory, differentiation and apoptotic signals in colonic epithelial cells. Our long-term goal is to understand the role of protein kinase C (PKC) isozymes in colonic epithelial cell biology and colon carcinogenesis. Several lines of evidence suggest that the atypical PKC iota isoform (PKCi) plays an important promotive role in colon carcinogenesis. First, PKC expression is elevated in colon tumors relative to uninvolved colonic epithelium. Second, expression of PKCi protects cancer cells from apoptosis by activating NF-kB. Third, PKCi plays a requisite role in the transformation of intestinal epithelial cells by activated Ras, an oncogene commonly mutated in colon cancer. Fourth, inhibition of PKCi activity by dietary omega-3 fatty acids correlates with the cancer-preventive effects of omega-3 fatty acids. Taken together these data indicate that PKCi plays a key role in colon carcinogenesis by enhancing cell survival. We hypothesize that PKCi protects colonic epithelial cells against apoptosis and that elevated PKCi in the colonic epithelium will result in an increased susceptibility to colon carcinogenesis. We have generated transgenic mice that express constitutively active (ca) or dominant-negative (dn) mutant forms of PKCi in the colonic epithelium and have detected a decrease in basal apoptosis in the colonic epithelium of mice expressing caPKCi. In Specific Aim 1, we will determine the role of PKCi in colonic epithelial cell homeostasis by further characterizing our caPKCi and dnPKCi transgenic mice. Specific Aim 2 will assess the role of PKCi in mediating the effects of K-ras on colonic epithelial cell homeostasis and colon carcinogenesis in-vivo. Specific Aim 3 will determine the role of PKCi in Ras transformation and NF-kB signaling in intestinal epithelial cells in-vitro and in the colonic epithelium in-vivo. Specific Aim 4 will assess the role of PKCi in dietary fat-mediated changes in colonic epithelial cell homeostasis and colon carcinogenesis. These aims will be accomplished through the use of complementary transgenic mouse and rat intestinal epithelial cell models to assess the function of PKCi in the colonic epithelium.

描述（由申请人提供）：结肠癌是由进行性进展引起的 正常生长抑制、分化和凋亡的失调 结肠上皮细胞中的信号。我们的长期目标是了解 蛋白激酶 C (PKC) 同工酶在结肠上皮细胞生物学中的作用 结肠癌发生。多项证据表明，非典型 PKC iota亚型（PKCi）在结肠癌发生中发挥重要的促进作用。 首先，相对于未受累的结肠肿瘤，PKC 表达升高 结肠上皮。其次，PKCi 的表达可以保护癌细胞免受 通过激活 NF-kB 来促进细胞凋亡。第三，PKCi 在 激活的癌基因 Ras 对肠上皮细胞的转化 结肠癌中常见突变。四、抑制PKCi活性 膳食 omega-3 脂肪酸与以下物质的预防癌症作用相关： omega-3 脂肪酸。综合这些数据表明 PKCi 发挥着关键作用 通过增强细胞存活在结肠癌发生中发挥作用。我们假设 PKCi 保护结肠上皮细胞免于凋亡并升高 PKCi 结肠上皮中的细菌会导致对结肠的敏感性增加 致癌作用。我们已经产生了组成型表达的转基因小鼠 结肠中 PKCi 的活性 (ca) 或显性失活 (dn) 突变形式 上皮细胞，并检测到结肠中基础细胞凋亡的减少 表达 caPKCi 的小鼠上皮细胞。在具体目标 1 中，我们将确定 进一步表征 PKCi 在结肠上皮细胞稳态中的作用 我们的 caPKCi 和 dnPKCi 转基因小鼠。具体目标 2 将评估 PKCi 介导 K-ras 对结肠上皮细胞稳态的影响 和体内结肠癌发生。具体目标 3 将确定以下角色： 肠上皮细胞中 PKCi 参与 Ras 转化和 NF-kB 信号传导 体外和体内结肠上皮。具体目标 4 将评估 PKCi 在膳食脂肪介导的结肠上皮细胞变化中的作用 体内平衡和结肠癌发生。这些目标将通过 使用互补转基因小鼠和大鼠肠上皮细胞 评估结肠上皮中 PKCi 功能的模型。