Nutritional Regulation of Catalase and Colorectal Cancer

描述(由申请人提供) 对癌症的易感性受饮食成分的影响。的确，饮食 富含脂肪、氮的铁会导致结直肠癌的高发病率， 涉及破坏肿瘤抑制功能的氧化应激。富含纤维 另一方面，谷物、蔬菜和水果等饮食会产生丁酸盐 在肠道中抑制发病率。之前的研究假设 丁酸盐在抑制肿瘤形成中的几个作用，但它是 仍不清楚丁酸盐如何与氧化剂和 抗氧化剂。研究人员的初步数据表明，在其 酪氨酸磷酸化，过氧化氢酶结合Grb2和Pl3Kp85调节蛋白 该过氧化氢酶包含一个共有的序列， “细胞因子信号抑制因子”，使其能够结合细长蛋白c，一个 核糖核酸合成延长的关键因素。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一种 过氧化氢酶与Grb2、Pl3Kp85和延伸素c的相互作用抑制氢 过氧化氢(过氧化氢)及其相关损害，否则将引发和 刺激结直肠癌。因此，理解丁酸盐依赖 过氧化氢酶调控应为控制结直肠癌提供新的策略 癌症。为了证明这一假设，提出了以下目标：(1)目标1 目的是确定过氧化氢酶与Grb2、Pl3Kp85和 (2)目标2的目的是表征 丁酸诱导的人结直肠癌细胞株过氧化氢酶。至 要实现这些目标，研究人员将确定：(A) 过氧化氢酶的突变会影响复合体的形成，(B) 使过氧化氢酶磷酸化的蛋白酪氨酸激酶上的丁酸盐，(C) 结合依赖性过氧化氢酶活性和氧化剂依赖性P53的变化 以及(D)丁酸诱导的过氧化氢酶的特性；即， 过氧化氢酶或胞质过氧化氢酶。这项研究假设一部小说和一部 过氧化氢酶活性由细胞信号调节的创新概念- 分子间缔合依赖机制。这项研究将允许 研究人员试图确定丁酸是如何调节过氧化氢酶活性的 以及它与信号分子的结合，这有助于控制细胞 有丝分裂和氧化剂依赖的肿瘤发生。

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.