aflatoxin 激活与解毒
中文名称
通路描述
黄曲霉毒素是黄曲霉和寄生曲霉等霉菌产生的主要次生代谢产物，污染了经济重要的粮食和饲料作物（Wild & Turner 2002）。黄曲霉毒素 B1（AFB1）是最强的天然致癌物之一，也是免疫抑制剂。它在许多物种中是强效的肝癌致癌剂，已被认为是人类肝细胞癌病因之一。家禽，特别是火鸡，对饲料中存在的 AFB1 的毒性和致癌作用极其敏感，导致行业损失数百万美元。阐明家禽对 AFB1 这种极端敏感性的生物化学和分子机制，将有助于开发增加 AFB1 耐性的新策略（Rawal et al. 2010, Diaz & Murcia 2011）。AFB1 的主要基因毒性代谢命运是转化为 AFXBO，还有其他一些较少致突变但仍有毒性的代谢产物。AFB1 可由几种细胞色素 P450 酶氧化为有毒的 AFB1 外环 8,9-环氧物（AFXBO），特别是肝脏中的 P450 3A4。该 8,9-环氧物可与 DNA 的鸟嘌呤 N7 原子反应，通过插入 DNA 碱基对之间形成加合物。外环环氧物在溶液中不稳定，可自发反应形成二醇，不再与 DNA 反应。二醇产物随后在碱催化下重排为二醛，可与蛋白质赖氨酸残基反应。AFB1 还可代谢为 AFQ1、AFM1、AFM1E 等产物，其基因毒性后果远小于 AFB1。AFB1 的主要解毒途径是其活性 8,9-环氧物与谷胱甘肽（GSH）结合。该反应由三聚谷胱甘肽转移酶（GSTs）执行，提供对毒性的化学保护机制。谷胱甘肽结合物通常以巯基乙酸的形式随尿液排出（Guengerich et al. 1998, Hamid et al. 2013）。人类黄曲霉毒素的主要代谢途径在此描述。
英文描述
Interleukin-2 signaling Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties.
IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c). The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells.
IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c). The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells.
所含基因
12 个基因