Mechanisms of the Adenovirus E4-ORF1 Oncoprotein

腺病毒 E4-ORF1 癌蛋白的机制

• 批准号: 7742648
• 负责人: Ronald T. Javier
• 金额: $ 31.71万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742648
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenoviruses; Animals; Anterior; Apical; BAIAP1 gene; Basal Cell; Binding; Cause of Death; Cell Polarity; Cell membrane; Cells; Complex; Defect; Developed Countries; Development; Disease; Elements; Embryonic Development; Epithelial Cells; Estrogens; Failure; Growth Factor; HPV-High Risk; Hand; Human; Human Adenoviruses; Human Development; Human T-lymphotropic virus 1; In Vitro; Incidence; Intercellular Junctions; Knowledge; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Molecular; Mus; Mutant Strains Mice; Oncogene Proteins; Oncogenic; Open Reading Frames; PDZ protein; Pathway interactions; Phosphoproteins; Process; Property; Proteins; Rattus; Research; Role; Signal Transduction; Staging; Taxes; Testing; Tight Junctions; Tumor Suppressor Proteins; Vesicle; Viral Proteins; Virus; Work; base; cancer cell; cell transformation; cellular targeting; in vivo; insight; metaplastic cell transformation; migration; monomer; novel; novel therapeutics; prevent; public health relevance; scaffold; stem; tool; trafficking; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The objective of work proposed in this application is to decipher important new mechanisms that trigger the development of human cancer. Among human adenoviruses, adenovirus type 9 is unique in causing exclusively estrogen-dependent mammary tumors in experimental animals and in having E4 region-encoded open reading frame 1 (E4-ORF1), rather than E1 region-encoded E1A and E1B, as its primary oncogenic determinant. Evidence indicates that the tumorigenic potential of E4-ORF1 depends on two separate protein-interaction elements, the PDZ domain-binding motif (PBM) and Domain 2 (D2). While D2 mediates binding to several unidentified cellular proteins, the PBM interacts with a select group of cellular PDZ proteins, including the three cell polarity proteins Dlg1, ZO-2, and PATJ, as well as the PATJ paralogue MUPP1 and MAGI-1. Underscoring the link of these cellular PDZ proteins to human cancer, Dlg1, PATJ, MUPP1, and MAGI-1 are also cellular targets of high-risk human papillomavirus E6 oncoproteins and Dlg1 is a cellular target of the human T-cell leukemia virus type 1 Tax oncoprotein. Our results lead to the hypothesis that the tumorigenic potential of E4-ORF1 stems from its combined capacities to induce Dlg1- and D2 protein-dependent constitutive PI3K activation and to block both PATJ- and ZO-2-dependent apical-basal cell polarity establishment and Dlg1-dependent anterior-posterior cell polarity establishment. This hypothesis will be tested by (Aim 1) purifying, identifying, and characterizing D2-interacting proteins and determining their role in disregulated PI3K signaling, (Aim 2) investigating tumor suppressor functions for PATJ and ZO-2 in mice, and (Aim 3) determining mechanisms for E4-ORF1-induced inhibition of anterior-posterior cell polarity. The immediate benefits of completing these aims will be the elucidation of novel mechanisms leading to tumorigenic activation of the PI3K pathway and loss of cell polarity. As both defects are hallmarks of cancer cells, this information should provide important new insights into the development of a wide variety of human malignancies. In the long-term, the knowledge gained from the proposed work may aid in the development of effective new therapeutic strategies to treat and prevent human cancers. PUBLIC HEALTH RELEVANCE: While cancer is a leading cause of death in developed countries, our understanding of the many different molecular mechanisms that trigger this complex disease remains somewhat limited. Two very common abnormalities of cancer cells are uncontrolled activation of the PI3K pathway and a failure to establish proper polarity. Given that we have identified a viral protein that promotes cancer by specifically causing these two defects, our research may reveal mechanisms underlying these important disease processes and thereby provide information that could be used to develop effective new therapies to treat and prevent a wide variety of human cancers.

描述（由申请人提供）：本申请中提出的工作的目的是破译引发人类癌症发展的重要新机制。在人类腺病毒中，腺病毒9型在实验动物中仅引起雌激素依赖性乳腺肿瘤的独特性，并且在具有E4区域编码的开放式阅读框架1（E4-ORF1）中，而不是E1区域编码的E1A和E1B，作为其主要的e1a和E1b，作为其主要的肿瘤性确定性。证据表明，E4-ORF1的致瘤潜力取决于两个独立的蛋白质相互作用元件，即PDZ结构域结合基序（PBM）和域2（D2）。 D2介导与几种未识别的细胞蛋白结合的结合，而PBM与一组精选的细胞PDZ蛋白相互作用，包括三种细胞极性蛋白DLG1，ZO-2和PATJ以及PATJ Paralogue Mupp1和Magi-1。强调这些细胞PDZ蛋白与人类癌，DLG1，PATJ，MUPP1和MAGI-1的联系也是高危人乳头瘤病毒E6癌蛋白和DLG1的细胞靶标，而DLG1是人类T-Cell Leukemia病毒1型1型税收蛋白的细胞靶标。我们的结果导致了以下假设：E4-ORF1的肿瘤型潜力源于其诱导DLG1-和D2蛋白依赖性的组成型PI3K激活的综合能力，并阻止PATJ-和ZO-2依赖性的顶端 - 依赖性的顶端 - 基体细胞极性建立以及DLGG1依赖性的Antererior-cellitior-Orterior-pollity-pollity-Orterior-Pallousmoumption。 This hypothesis will be tested by (Aim 1) purifying, identifying, and characterizing D2-interacting proteins and determining their role in disregulated PI3K signaling, (Aim 2) investigating tumor suppressor functions for PATJ and ZO-2 in mice, and (Aim 3) determining mechanisms for E4-ORF1-induced inhibition of anterior-posterior cell polarity.完成这些目标的直接好处将是阐明新机制，导致PI3K途径的肿瘤性激活和细胞极性的丧失。由于两个缺陷都是癌细胞的标志，因此该信息应为各种人类恶性肿瘤的发展提供重要的新见解。从长远来看，从提议的工作中获得的知识可能有助于制定有效的新治疗策略来治疗和预防人类癌症。公共卫生相关性：虽然癌症是发达国家的主要死亡原因，但我们对触发这种复杂疾病的许多不同分子机制的理解仍然有限。癌细胞的两个非常常见的异常是PI3K途径的不受控制的激活，并且无法建立适当的极性。鉴于我们已经确定了一种病毒蛋白，该病毒蛋白通过特异性引起这两个缺陷来促进癌症，因此我们的研究可能揭示了这些重要疾病过程的机制，因此提供了可用于开发有效治疗和预防各种人类癌症的有效疗法的信息。