Oxidative stress and ikBalpha modification

描述（由申请人提供） 转录因子NFkB是细胞应答中的关键因子 应对各种压力 NFkB激活与细胞凋亡相关 增殖并发生在许多肿瘤中。 调查人员表明， 过氧化物酶体增殖物，其引起氧化应激并作为肝脏 啮齿类动物中的致癌物，可以激活肝脏中的NFkB。 这种激活可以 会被抗氧化剂阻断。 NFkB的激活是由一个信号传导介导的。 导致磷酸化和随后的多聚泛素化的途径 和IkB的降解。 最近，几个小组已经使用体外系统 为了表明SUMO可以以类似于以下的方式缀合至IkBa： 这个分子的多聚泛素化。 这些研究引起了人们的兴趣。 SUMO修饰形式的IkBa可能参与细胞凋亡， 对压力的反应。 研究人员已经确定了一种新形式的IkBa， 已经用过氧化物酶体增殖剂处理的小鼠的肝脏。 这 修饰与这是SUMO修饰的可能性一致。 Ikba的形式。 他们推测，这种新形式的IkBa可能是一种 NFkB信号转导的重要调节因子， 过氧化物酶体增殖物。 在这项拨款中，他们建议将 在用过氧化物酶体处理的小鼠肝脏中缓慢迁移的IkBa形式 并确定这是否确实是由于SUMO修饰。 此外，由于这种新的IkBa形式是通过长期治疗诱导的， 过氧化物酶体增殖物，已知会引起氧化应激， 研究人员将确定这种新的IkBa是否可以通过 膳食抗氧化剂。 总的来说，这些研究可能有助于阐明其他 在生物体中控制NFkB活性的机制。

DESCRIPTION (provided by applicant) The transcription factor, NFkB, is a critical factor in the cellular response to various types of stress. NFkB activation is associated with cell proliferation and occurs in many tumors. The investigators have shown that peroxisome proliferators, which cause oxidative stress and act as hepatic carcinogens in rodents, can activate NFkB in the liver. This activation can be blocked by antioxidants. NFkB activation is mediated by a signaling pathway that leads to the phosphorylation and subsequent polyubiquitination and degradation of IkB. Recently, several groups have used in vitro systems to show that the SUMO can be conjugated to IkBa in a manner that is similar to polyubiquitination of this molecule. These studies raise the interesting possibility that SUMO-modified forms of IkBa may be involved in the cellular response to stress. The investigators have identified a novel form of IkBa that is found in the livers of mice that have been treated with peroxisome proliferators. This modification is consistent with the possibility that this is a SUMO-modified form of IkBa. They hypothesize that this novel form of IkBa may be an important regulator of NFkB signaling in the livers of mice treated with peroxisome proliferators. In this grant, they propose to characterize the slower migrating form of IkBa in the livers of mice treated with peroxisome proliferators and determine whether this indeed is due to SUMO-modification. In addition, since this novel IkBa form is induced by long-term treatment with peroxisome proliferators, which are known to cause oxidative stress, the investigators will determine whether this novel IkBa can be modulated by dietary antioxidants. Overall, these studies may help elucidate additional mechanisms that control NFkB activity in organisms.