Role of sestrin family genes in antioxidant defense

描述（由申请人提供）：活性氧（Reactive oxygen species， ROS）不仅是代谢过程中需要消除的有害副产物，而且是在许多信号通路中服务的重要信使。作为一个信号，ROS通过过度氧化过氧化物氧化酶（Prxs）来规避抗氧化防御，Prxs是代谢过氧化物的酶。然而，在信号传递后，需要恢复抗氧化防火墙以防止氧化应激。最近我们发现，由p53肿瘤抑制因子（Hi95和PA26基因）调控表达的sestrins家族蛋白，在含有半胱氨酸亚磺酸的过度氧化Prxs的再生中是必需的，从而重建抗氧化防御。抑制乙酰丝氨酸导致严重的氧化应激，导致细胞凋亡或过早衰老。我们假设，作为抗氧化防御和ros相关信号传导的关键调节剂，sestrins可能决定细胞类型对促氧化治疗的特异性反应，以及信号传导的结果，因此代表了ros相关病理治疗的有吸引力的靶点。在本项目中，我们将通过研究参与过氧化物催化的蛋白伴侣、不同水平上的sestrin基因调控机制、sestrin活性和细胞内定位随应激和各种生理信号的变化来确定sestrin蛋白抗氧化活性的分子机制。我们将研究促凝素家族基因在正常生理信号调节中的作用，以及在应激条件下决定细胞命运的作用。我们将通过分析Hi95、PA26和SesnS不同亚型的表达水平、细胞内定位和比例对信号转导效率的影响，来研究sestrin基因在细胞因子信号传导中的作用。通过分析sestrin基因响应p53的调控模式，我们将阐明它们在保护基因组免受氧化损伤中的作用，以及它们在p53介导的遗传稳定性控制中的作用。我们将在转基因和敲低小鼠模型中探讨凝集素在发育和机体反应中的作用。在肺癌模型中，将评估凝集素在癌症发生中的潜在作用。该结果将提供一个估计的潜在价值的凝集素作为治疗干预的目标。

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) are not only harmful by-products of metabolism that need be eliminated to prevent injury, but also important messengers serving in numerous signaling pathways. Acting as a signal, ROS circumvents antioxidant defense by overoxidizing peroxiredoxins (Prxs), the enzymes metabolizing peroxides. However, after the signal is conveyed the antioxidant firewall needs to be restored to prevent oxidative stress. Recently we found that sestrins, a family of proteins whose expression is modulated by p53 tumor suppressor (Hi95 and PA26 genes), are required for regeneration of the over-oxidized Prxs containing cysteine sulfinic acid, thus reestablishing the antioxidant defense. Inhibition of sestrins leads to severe oxidative stress, resulting in apoptosis or premature senescence. We hypothesize that sestrins being critical modulators of both antioxidant defense and ROS-related signaling might determine cell type specific responses to pro-oxidant treatments, and the outcome of signaling, thus representing attractive targets for therapy of ROS-related pathologies. In the proposed program, we are going to determine molecular mechanisms of antioxidant activity of sestrin proteins by studying the protein partners involved in the catalysis of peroxides, the mechanisms of sestrin gene regulation at different levels, the changes in the activity and intracellular localization of sestrins depending on stresses and various physiological signals. We are going to study the roles of sestrin family genes in the modulation of normal physiological signaling, as well as in determining cell fate during stress. We shall study the role of sestrin genes in the cytokine signaling by analyzing the efficiency of signal transduction depending on the levels of expression, intracellular localization, and the proportions of different isoforms of Hi95, PA26 and SesnS. By analyzing the modes of regulation of sestrin genes in response to p53, we will elucidate their role in the protection of the genome against oxidative damage, and their contribution to the p53-mediated control of genetic stability. Roles of sestrins in development and organismic responses will be explored in transgenic and knockdown mouse models. The potential involvement of sestrins in cancerogenesis will be evaluated in a lung cancer model. The results will provide an estimate of the potential value of sestrins as targets for therapeutic interventions.