Apoptosis Regulation by Adenovirus and Cellular Genes

描述（由申请方提供）：在感染小DNA肿瘤病毒的细胞中，细胞凋亡的发生是由病毒早期蛋白诱导非程序细胞DNA合成触发的。在人腺病毒（Adv）感染的细胞中，早期区域E1 A编码的蛋白在诱导细胞凋亡中起核心作用，并且该过程被BCL-2的病毒同源物E1 B-19 K积极抑制。Adv诱导细胞凋亡的研究已成为其他病毒感染诱导细胞凋亡的模型. Adv也是一个有价值的工具来剖析细胞凋亡调节因子的正常和病理功能。在Adv-induced细胞凋亡，BH 3-唯一的蛋白BIK功能作为顶端效应。BIK介导的凋亡信号传导导致多结构域（BH 1 -3）促凋亡成员BAX和巴克的活化。目前的更新申请将集中在解开两个E1 B-19 K靶向BH 3-only分子BIK和BNIP 3，以及BH 1 -3分子巴克和BAX在动物模型和癌症发展中病毒诱导的细胞凋亡和细胞凋亡损伤中的功能。在目的1中，我们将研究Bik通过E2 F-1依赖性途径的转录激活模式，这是一种通过与pRB相互作用的病毒癌基因激活BIK的新的转录后模式。将在Bik缺失小鼠模型中研究病毒诱导的细胞凋亡在Adv-induced细胞凋亡肝损伤中的作用。我们还将使用免疫缺陷小鼠模型来评估抗凋亡疗法以抑制病毒诱导的肝损伤。我们推测，在病毒感染的晚期，病毒可能利用细胞凋亡进行细胞间扩散。我们的研究结果表明，BAX和巴克可能在病毒外出和传播中具有新的功能。在目标2中，我们将使用Adv来阐明BAX和巴克的新功能，它们通过这些功能促进或限制病毒传播。临床结果和实验证据表明，E1 B-19 K靶分子BNIP 3在实体瘤如肺癌和乳腺癌的发展中起着重要作用。在目标3中，我们将使用Bnip 3敲除小鼠和条件性p53-Rb 1 KO肺癌小鼠模型研究BNIP 3在肿瘤发生和进展中的作用。在这个目标中，我们还将研究BNIP 3在调节腺病毒诱导的自噬和自噬细胞死亡中的作用。我们对这些关键细胞凋亡调节因子的研究可能为它们在病毒诱导的细胞凋亡、病毒传播和发病机制中的作用提供重要的新见解。这些结果将对其他病毒和病原体感染具有广泛的相关性。对E1 B-19 K靶分子BNIP 3和BIK的拟议研究可能阐明它们在肺癌、乳腺癌和结肠癌的发展和进展中的作用，并可能提出抑制肿瘤发生和肿瘤进展的策略。

DESCRIPTION (provided by applicant): In cells infected with small DNA tumor viruses, the onset of apoptosis is triggered by the induction of unscheduled cellular DNA synthesis by viral early proteins. In cells infected with human adenoviruses (Adv), the proteins coded by the early region E1A play a central role in inducing apoptosis and the process is actively suppressed by E1B-19K which is a viral homolog of BCL-2. Studies on Adv- induced apoptosis have served as the model for apoptosis induced by other viral infections. Adv also serves as a valuable tool to dissect the normal and pathological functions of apoptosis regulators. During Adv-induced apoptosis, the BH3-only protein BIK functions as the apical effector. BIK-mediated apoptosis signaling results in the activation of multi-domain (BH1-3) pro-apoptotic members BAX and BAK. The present renewal application will focus on unraveling the functions of two E1B-19K target BH3-only molecules BIK and BNIP3, and the BH1-3 molecules BAK and BAX in virus-induced apoptosis and apoptotic injury in an animal model and in cancer development. In Aim 1, we will investigate the mode of transcriptional activation of Bik through an E2F-1 dependent pathway, a novel post- transcriptional mode of activation of BIK by viral oncogenes that interact with pRB. The role of virus- induced apoptosis in Adv-induced apoptotic liver damage will be investigated in the Bik-null mouse model. We will also use an immunodeficient mouse model to evaluate anti-apoptosis therapeutics to inhibit virus-induced hepatic injury. We have postulated that viruses may exploit apoptosis for intercellular spread during late stages of viral infection. Our results suggest that BAX and BAK may have novel functions in viral egress and spread. In Aim 2, we will use Adv to elucidate novel functions of BAX and BAK by which they promote or restrict viral spread. Clinical results and experimental evidence suggest that the E1B-19K target molecule BNIP3 plays a fundamental role in the development of solid tumors such as lung and breast carcinomas. In Aim 3, we will investigate the role of BNIP3 in tumor development and progression using Bnip3 knockout mouse and a conditional p53-Rb1 KO lung cancer mouse model. In this Aim, we will also investigate the roles of BNIP3 in regulating Adv-induced autophagy and autophagic cell death. Our proposed studies on these critical cellular apoptosis regulators may provide important new insights on their role in virus-induced apoptosis, viral spread and pathogenesis. These results will have broad relevance to other virus and pathogen infections. The proposed studies on the E1B-19K target molecules BNIP3 and BIK may illuminate their roles in the development and progression of lung, breast and colon cancers and may suggest strategies to inhibit tumorigenesis and tumor progression.