Deregulation of Cell Pathways by Ad E1B 55K Oncoproteins

Ad E1B 55K 癌蛋白对细胞通路的失调

• 批准号: 6515186
• 负责人: DAIQING LIAO
• 金额: $ 27.08万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515186
• 关键词: Adenoviridae; acetylation; cell growth regulation; centrosome; genetic promoter element; guanine nucleotide binding protein; host organism interaction; microorganism culture; oncoproteins; p53 gene /protein; posttranslational modifications; protein protein interaction; telomere; ubiquitin; viral carcinogenesis; virus infection mechanism; virus protein

DESCRIPTION: (provided by applicant) Cancer arises through specific genetic changes in somatic cells. Major events include inactivating both p53 and pRb pathways, activating oncogenes such as ras, and telomere maintenance. Such genetic events may also be reflected in cells transformed by tumor viruses. For example, several viral oncogenes, such as the simian virus 40 large-T antigen, the human papillomavirusl6 E6 and E7 oncoproteins, and the adenovirus (Ad) E1A and E1B proteins, can effectively inactivate the p53 and pRb pathways. In addition, these multifunctional viral oncogenes can perturb other cell pathways, which may contribute to cell transformation. p53 is a prototypic tumor suppressor that is frequently mutated in diverse human cancers. It exerts its tumor suppression function largely through transactivation of genes containing specific p53- binding DNA sequences within their promoters. The p53 target genes are involved in cell cycle arrest and apoptosis, two major mechanisms in tumor suppression. Viral oncoproteins employ different strategies to inactivate p53, ranging from interference with p53-DNA interaction to promoting p53 degradation. We demonstrated recently that Ad E1B 55-kDa proteins repress p53 transactivation by specifically inhibiting acetylation of p53 by acetylase PCAF. As p53 acetylation at specific lysine residues by PCAF and p300 is crucial for its transactivation function and its ability to suppress cell transformation, inhibition of p53 acetylation by E1B impairs its function. We will determine the biological significance of p53 acetylation by these acetylases and mechanism(s) by which E1B inhibits p53 acetylation. We have found that E1B binds to PCAF and p300. We will determine the importance of such interactions for E1B to inhibit p53 acetylation by these acetylases, and how E1B may affect their functions. We also found that E1B interferes with p53-dependent and -independent cell cycle checkpoints. We will determine potential mechanisms underlying such interference. Additionally, p53 protein levels are elevated in cells expressing EIB, which may be a consequence of perturbing ubiquitin-dependent proteolysis by E1B, as we found that it binds to a variant of UbcH7, a ubiquitin conjugating enzyme that is involved in ubiquitination of certain cellular proteins including p53. We will elucidate how E1B perturbs this pathway. These studies will enhance our understanding of cell transformation and cancer.

描述：（由申请人提供）癌症是通过特定的遗传 体细胞的变化。主要事件包括p53和pRb失活 途径，激活癌基因如ras和端粒维持。等 遗传事件也可以反映在由肿瘤病毒转化的细胞中。为 例如，几种病毒癌基因，如猿猴病毒40大T抗原， 人乳头瘤病毒16 E6和E7癌蛋白，以及腺病毒（Ad）E1 A 和E1 B蛋白，可以有效地阻断p53和pRb通路。在 此外，这些多功能病毒癌基因可以干扰其他细胞， 这可能有助于细胞转化。p53是一种典型的 在多种人类癌症中经常突变的肿瘤抑制因子。它施加 其肿瘤抑制功能主要通过基因反式激活来实现 在其启动子内含有特异性p53结合DNA序列。的p53 靶基因参与细胞周期阻滞和凋亡，这两个主要的 肿瘤抑制机制。病毒癌蛋白采用不同的策略 对p53的干扰，从干扰p53-DNA相互作用到 促进p53降解。我们最近证明，Ad E1 B 55-kDa蛋白 通过特异性抑制p53的乙酰化来抑制p53的反式激活， 乙酰化酶PCAF。由于p53通过PCAF和p300在特定赖氨酸残基处乙酰化 对于其反式激活功能和抑制细胞增殖能力是至关重要的 转化，通过E1 B抑制p53乙酰化损害其功能。我们 将确定p53乙酰化的生物学意义， 乙酰化酶和E1 B抑制p53乙酰化的机制。我们有 发现E1 B与PCAF和p300结合。我们将确定这样的重要性 E1 B通过这些乙酰化酶抑制p53乙酰化的相互作用，以及如何 E1 B可能会影响其功能。我们还发现，E1 B干扰 p53依赖和非依赖细胞周期检查点。我们将确定 这种干扰的潜在机制。p53蛋白 在表达EIB的细胞中水平升高，这可能是 通过E1 B干扰泛素依赖的蛋白水解，因为我们发现它结合到 UbcH 7的一种变体，UbcH 7是一种泛素结合酶， 包括p53在内的某些细胞蛋白的泛素化。我们将阐明 E1 B是如何干扰这条通路的。这些研究将增进我们对 细胞转化和癌症。