Adenovirus E1B55K Functions Related to Oncolytic Replication

腺病毒 E1B55K 与溶瘤复制相关的功能

• 批准号: 8009780
• 负责人: Heshan Sam ZHOU
• 金额: $ 26.81万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009780
• 关键词: Adenovirus Infections; Adenovirus Protein; Adenoviruses; Affect; Apoptosis; Binding; Cancer Etiology; Cell Cycle; Cell Proliferation; Clinical Trials; Cyclin E; DNA biosynthesis; E2F Transcription Factor 1; E2F transcription factors; Genes; Goals; Health; Human papillomavirus 16 E1 protein; In Vitro; Laboratories; Malignant Neoplasms; Mediating; Molecular; Mus; Mutate; Mutation; Normal Cell; Oncogene Proteins; Oncogenes; Oncolytic; Oncolytic viruses; Outcome; Pathway interactions; Patients; Process; Proteins; Publishing; Regulation; Research; Retinoblastoma Protein; Role; Site; Testing; Treatment Efficacy; Viral; Viral Physiology; Virus; Virus Replication; Work; Xenograft Model; base; cancer cell; cellular targeting; clinical application; gene therapy; genetic analysis; in vivo; killings; mutant; novel; oncolysis; overexpression; promoter; response; tumor; viral DNA

DESCRIPTION (provided by applicant): Two major "hallmarks" of all cancer cells include dysregulated cell cycle and inhibited apoptosis, both of which are also involved in adenovirus (Ad) infection. These two processes are primarily conducted by viral oncoproteins E1A and E1B. Since the function of viral E1 protein is similar to that of cancer cellular factors that promote proliferation and inhibit apoptosis, viruses with mutations in oncoprotein E1A and E1B can selectively replicate in cancer cells. One such mutant with deletion of E1B55K, known as dl1520, has been used in clinical trials documenting oncolytic effects. However, the mechanism of viral oncolytic replication has not been well characterized, and the therapeutic efficacy needs improvement. It is generally believed that the major role of E1B55K is to bind to and inhibit p53 activation, but many studies have documented that E1B55K-mediated p53 inactivation is not required for virus replication. Our laboratory has shown: (1) that the limited spread of mutant viruses in large tumors is a key factor in decreased therapeutic efficacy; (2) increased Ad E1A expression enhances virus-oncolytic replication; and (3) apoptosis caused by E1B deletion can partially decrease virus replication but does not change the final outcome of virus-mediated cancer killing. Our recent studies have revealed that E1B55K has a novel function in the induction of cyclin E and other cell cycle-related genes. Most importantly, we also observed that increased cyclin E expression is correlated with virus replication efficiency. E1B55K-induced cyclin E expression is required for virus replication in normal cells, but is not necessary in cancer cells. We hypothesize that E1B55K may target cellular factor(s) to increase cyclin E expression, and this factor(s) may already be activated in cancer cells. Thus, cyclin E dysregulation in cancer cells may be the molecular basis for oncolytic replication of E1B55K-deleted viruses. Our research team will (1) identify cellular factors targeted by E1B55K for cyclin E induction, (2) define the mechanism by which E1B55K activates cyclin E expression, and (3) determine the relationship between cyclin E overexpression and oncolytic replication of E1B-deleted viriuses. If we confirm that oncolytic replication relies on cyclin E expression and cell proliferation, patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy. PUBLIC HEALTH RELEVANCE: Adenoviruses lacking an important regulative protein-E1B55K-still can amplify in some cancer cells. Therefore, the E1B55K mutant dl1520 has been used in clinical trials. It is important to understand the E1B55K function and the selective replication of E1B55K-deleted dl1520 in cancer cells. Our recently published studies have revealed that E1B55K has a novel function in the induction of cyclin E expression, which is crucial for DNA replication. Cancer cells generally express high levels of cyclin E or have a dysregulation of the gene. We reason that viral E1B55K may activate some cellular factors that increase cyclin E expression for viral DNA replication. Cancer cells may already have the factors activated; therefore cancer cells do not require the E1B55K function. The study of this possibility is very important. If we confirm that mutated virus replication relies on cyclin E expression, patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy.

描述（由申请人提供）：所有癌细胞的两个主要“标志”包括失调的细胞周期和抑制细胞凋亡，这两者也涉及腺病毒（AD）感染。这两个过程主要由病毒癌蛋白E1A和E1B进行。由于病毒E1蛋白的功能与促进增殖并抑制凋亡的癌细胞因子的功能相似，因此在癌细胞中具有突变的病毒可以在癌细胞中有选择地复制。一种具有E1B55K缺失的突变体，称为DL1520，已用于记录溶瘤作用的临床试验中。然而，病毒性溶瘤复制的机制尚未得到很好的特征，并且治疗功效需要提高。人们普遍认为，E1B55K的主要作用是结合并抑制p53的激活，但许多研究表明，E1B55K介导的p53失活并不需要病毒复制。我们的实验室表明：（1）突变病毒在大肿瘤中的传播有限是治疗功效降低的关键因素； （2）增加的AD E1a表达增强了病毒 - 溶质的复制； （3）由E1B缺失引起的凋亡可以部分降低病毒复制，但不会改变病毒介导的癌症杀伤的最终结果。我们最近的研究表明，E1B55K在诱导细胞周期E和其他细胞周期相关基因方面具有新的功能。最重要的是，我们还观察到，细胞周期蛋白E表达的增加与病毒复制效率相关。 E1B55K诱导的细胞周期蛋白E表达是正常细胞中病毒复制所必需的，但在癌细胞中不需要。我们假设E1B55K可能靶向细胞因子以增加细胞周期蛋白E的表达，并且该因子可能已经在癌细胞中被激活。因此，癌细胞中的细胞周期蛋白E失调可能是E1B55K骨骨化病毒的溶瘤复制的分子基础。我们的研究团队将（1）确定E1B55K靶向细胞周期蛋白E诱导的细胞因子，（2）定义了E1B55K激活细胞周期蛋白E表达的机制，（3）确定细胞周期蛋白E过表达与E1B骨骼骨骼病毒性的溶液化复制之间的关系。如果我们确认溶瘤复制依赖于细胞周期蛋白E的表达和细胞增殖，则积极生长肿瘤和失调的细胞周期蛋白E的患者应从这种腺病毒疗法中受益匪浅。这项工作的长期目标是提高溶瘤癌基因治疗的功效。公共卫生相关性：缺乏重要的调节性蛋白质-E1B55K-Still的腺病毒可以在某些癌细胞中放大。因此，E1B55K突变体DL1520已用于临床试验。重要的是要了解E1B55K函数和癌细胞中E1B55K删除的DL1520的选择性复制。我们最近发表的研究表明，E1B55K在诱导细胞周期蛋白表达的功能方面具有新的功能，这对于DNA复制至关重要。癌细胞通常表达高水平的细胞周期蛋白或基因失调。我们认为，病毒E1B55K可能会激活一些细胞因子，从而增加细胞周期蛋白E表达的病毒DNA复制。癌细胞可能已经激活了因素。因此，癌细胞不需要E1B55K功能。对这种可能性的研究非常重要。如果我们确认突变的病毒复制取决于细胞周期蛋白E的表达，则积极生长的肿瘤和失调的细胞周期蛋白E应该从这种腺病毒疗法中受益匪浅。这项工作的长期目标是提高溶瘤癌基因治疗的功效。