Nutritional Regulation of Catalase and Colorectal Cancer

描述（由申请人提供） 癌症的易感性受饮食成分的影响。 事实上， 富含脂肪、氮铁导致大肠癌发病率高， 涉及损害肿瘤抑制功能的氧化应激。 富含纤维 另一方面，谷物、蔬菜和水果等饮食产生丁酸盐， 来抑制发病率 先前的研究假设 丁酸盐在抑制肿瘤发生中的几种作用，但它是 目前还不清楚丁酸盐是如何与氧化剂的调节有关的， 抗氧化剂 研究人员的初步数据表明， 酪氨酸磷酸化，过氧化氢酶结合Grb2和Pl3Kp85，调节蛋白 过氧化氢酶含有一个共有序列， “细胞因子信号转导抑制因子”，使其能够结合延伸蛋白c， RNA合成延长的必要因子。 重要的是，丁酸盐 诱导过氧化氢酶并抑制其酪氨酸磷酸化和结合。 因此，假设丁酸诱导过氧化氢酶并调节过氧化氢酶活性。 过氧化氢酶与Grb 2、Pl3 Kp85和elongin c相互作用抑制氢 过氧化氢（H2O2）及其相关损害，否则会引发和 刺激结肠直肠癌。 因此，了解丁酸依赖性 过氧化氢酶调节应提供控制结直肠癌的新策略 癌 为了证明这一假设，本文提出了以下目标：（1）目标1 是为了确定过氧化氢酶与Grb2，P13Kp85， （2）目的二是研究抗氧化剂的抗氧化特性， 丁酸盐在人结肠直肠癌细胞系中诱导的过氧化氢酶。 到 为了实现这些目标，研究人员将确定：（a） 过氧化氢酶，其突变影响复合物的形成，（B） 丁酸对磷酸化过氧化氢酶的蛋白酪氨酸激酶的作用，（c）丁酸对磷酸化过氧化氢酶的蛋白酪氨酸激酶的作用， 过氧化氢酶活性和氧化剂依赖性p53的结合依赖性改变 激活，和（d）丁酸盐诱导的过氧化氢酶的特性;即， 过氧化物酶体或胞质过氧化氢酶。 这项研究假设了一部小说， 创新概念过氧化氢酶活性受细胞信号传导调节- 和分子间缔合依赖机制。 这项研究将使 研究人员确定丁酸盐如何调节过氧化氢酶活性 以及它与信号分子的结合， 有丝分裂和氧化剂依赖性肿瘤发生。

DESCRIPTION (provided by applicant) Susceptibility to cancer is influenced by dietary components. Indeed, diets rich in fat, nitrogen iron cause a high incidence of colorectal cancer, involve oxidative stress that impairs tumor suppressor function. Fiber-rich diets such as grain, vegetable and fruits, on the other hand, produce butyrate in the gut to suppress the incidence. Previous studies have postulated several roles for butyrate in the suppression of tumorigenesis, but it is still unclear how butyrate is linked to the regulation of oxidants and antioxidants. The researchers' preliminary data suggest that, upon its tyrosine phosphorylation, catalase binds Grb2 and Pl3Kp85, regulatory proteins of insulin signaling, and that catalase contains a consensus sequence of "suppressor of cytokine signaling" that enables it to bind elongin c, an essential factor for elongation of RNA synthesis. Importantly, butyrate induces catalase and suppresses its tyrosine phosphorylation and binding. Therefore, it is hypothesized that butyrate induces catalase and regulates an interaction of catalase with Grb2, Pl3Kp85 and elongin c to suppress hydrogen peroxide (H2O2) and its related damage, that would otherwise initiate and stimulate colorectal cancer. Thus, understanding the butyrate-dependent catalase regulation should provide new strategies to control colorectal cancer. To prove this hypothesis, the following aims are proposed: (1) Aim 1 is to determine the mechanisms of catalase binding with Grb2, Pl3Kp85, and elongin c, and the control by butyrate; (2) Aim 2 is to characterize the catalase that butyrate induces in human colorectal cancer cell line. To achieve these goals, the researchers will determine: (a) the binding sites of catalase whose mutation affects the complex formation, (b) the effects of butyrate on protein tyrosine kinase that phosphorylates catalase, (c) the binding-dependent alteration of catalase activity and oxidant-dependent p53 activation, and (d) the identities of catalase that butyrate induces; i.e., peroxisomal or cytosolic catalase. This study postulates a novel and innovative concept that catalase activity is modulated by a cell signaling- and intermolecular association-dependent mechanism. This research will allow the investigators to establish how butyrate regulates the catalase-activity and its binding with signaling molecules, that contribute to control cell mitogenesis and oxidant-dependent tumorigenesis.