Deregulation of Cell Pathways by Ad E1B 55K Oncoproteins

描述：(申请人提供)癌症是由特定的基因引起的 体细胞的变化。重大事件包括使P53和pRb失活 途径，激活癌基因，如ras，和端粒维持。是这样的 遗传事件也可能反映在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E6和E7癌蛋白以及腺病毒(Ad)E1a 和E1B蛋白，可以有效地灭活P53和pRB通路。在……里面 此外，这些多功能的病毒癌基因还可以干扰其他细胞 途径，这可能有助于细胞转化。P53是一个原型 肿瘤抑制因子，在多种人类癌症中经常发生突变。它会使你 它的肿瘤抑制作用主要是通过基因的反式激活来实现的 在它们的启动子中包含特定的P53结合DNA序列。P53 靶基因涉及细胞周期停滞和凋亡，这是两个主要的 肿瘤抑制的机制。病毒癌蛋白采用不同的策略 使P53失活，从干扰P53-DNA相互作用到 促进P53降解。我们最近证实了Ad E1B 55-kDa蛋白 通过特异性抑制P53的乙酰化抑制P53的反式激活 乙酰酶PCAF。PCAF和p300在特定赖氨酸残基上的乙酰化作用 对其转录激活功能和抑制细胞的能力至关重要 E1B对P53乙酰化的抑制作用削弱了其功能。我们 将通过这些决定P53乙酰化的生物学意义 乙酰酶及E1B抑制p53乙酰化的机制(S)。我们有 发现E1B与PCAF和p300结合。我们将确定这样的重要性 E1B通过这些乙酰化酶抑制P53乙酰化的相互作用及其机制 E1B可能会影响它们的功能。我们还发现E1B干扰了 P53依赖和独立的细胞周期检查点。我们将决定 这种干扰背后的潜在机制。此外，P53蛋白 表达EIB的细胞中水平升高，这可能是 E1B干扰泛素依赖的蛋白分解，因为我们发现它结合到 UbcH7的变种，UbcH7是一种泛素结合酶，参与 某些细胞蛋白的泛素化，包括P53。我们会澄清 E1B是如何干扰这一途径的。这些研究将加深我们对 细胞转化和癌症。

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.