Role of sestrin family genes in antioxidant defense

描述（由申请人提供）：活性氧（ROS）不仅是代谢的有害副产物，需要消除以防止损伤，而且是许多信号通路中的重要信使。作为一种信号，ROS通过过氧化过氧化物酶（Prxs）（代谢过氧化物的酶）来规避抗氧化防御。然而，在信号传递后，需要恢复抗氧化剂防火墙以防止氧化应激。最近，我们发现，sestrins，一个家庭的蛋白质，其表达是由p53肿瘤抑制基因（Hi95和PA26基因）的调控，需要再生的过氧化的Prxs含有半胱氨酸亚磺酸，从而重建抗氧化防御。抑制sestrins导致严重的氧化应激，导致细胞凋亡或过早衰老。我们假设，sestrins是抗氧化防御和ROS相关信号传导的关键调节剂，可能决定细胞类型对促氧化剂治疗的特异性反应，以及信号传导的结果，因此代表了ROS相关病理学治疗的有吸引力的靶点。在本研究中，我们将通过研究参与过氧化物酶催化的蛋白质伴侣、sestrin基因在不同水平上的调控机制、sestrin活性的变化以及sestrin在细胞内的定位，来确定sestrin蛋白抗氧化活性的分子机制。我们将研究sestrin家族基因在调节正常生理信号中的作用，以及在压力下决定细胞命运的作用。我们将研究sestrin基因在细胞因子信号传导中的作用，通过分析取决于表达水平、细胞内定位以及Hi95、PA26和SesnS的不同亚型的比例的信号传导效率。通过分析sestrin基因在p53应答中的调控模式，我们将阐明它们在保护基因组免受氧化损伤中的作用，以及它们对p53介导的遗传稳定性控制的贡献。 将在转基因和敲除小鼠模型中探索sestrins在发育和器官反应中的作用。将在肺癌模型中评估sestrin在癌症发生中的潜在参与。这些结果将提供sestrins作为治疗干预靶点的潜在价值的估计。

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.