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首页> 外文学位 >HPV-16 E6 and E7 disrupt cell proliferation and apoptosis control mechanisms in normal human cells.
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HPV-16 E6 and E7 disrupt cell proliferation and apoptosis control mechanisms in normal human cells.

机译：HPV-16 E6和E7破坏正常人细胞中的细胞增殖和凋亡控制机制。

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摘要

The high risk human papillomaviruses are implicated in the etiology of most human cervical carcinomas. This thesis describes investigations of the ability of the HPV type 16 E6 and E7 oncoproteins to interfere with specific cellular proliferation and apoptosis control mechanisms in normal diploid human fibroblasts. Mitotic checkpoints were first examined. These checkpoints maintain genomic stability and, thus, likely act to limit carcinogenesis. HPV-16 E6 expression decreased the fidelity of multiple mitotic checkpoints. After irradiation, nearly 50% of cells containing HPV-16 E6 entered mitosis as opposed to less than 10% of control cells. Consistent with this, asynchronous cell populations expressing HPV-16 E6 had increased cdc2-associated kinase activity relative to control populations. In addition, cell populations expressing HPV-16 E6 displayed decreased mitotic spindle assembly checkpoint function and an increased tendency to undergo chemically-induced S-phase premature mitosis. HPV-16 E6 mutants with a reduced ability to target p53 for degradation did not abrogate mitotic checkpoints and expression of dominant negative p53 mutant genes also generated decreases in mitotic checkpoint function, suggesting HPV-16 E6 disrupts mitotic checkpoints in part through inactivating p53.;In addition to mitotic checkpoint disruption, activities encoded by the HPV interfere with apoptosis signal transduction pathways. Apoptosis is both an important component of host antiviral defenses and can suppress tumorigenesis. The HPV-16 E7 oncoprotein inhibits apoptosis signal transduction initiated by the antiviral cytokine, tumor necrosis factor-
机译：高风险的人乳头瘤病毒与大多数人宫颈癌的病因有关。本论文描述了HPV 16型E6和E7型癌蛋白干扰正常二倍体人成纤维细胞中特定细胞增殖和凋亡控制机制的能力。首先检查有丝分裂检查点。这些检查点保持基因组稳定性，因此可能会限制癌变。 HPV-16 E6表达降低了多个有丝分裂检查点的保真度。照射后，将近50％的含有HPV-16 E6的细胞进入有丝分裂，而少于10％的对照细胞进入有丝分裂。与此相一致，相对于对照种群，表达HPV-16 E6的异步细胞种群具有与cdc2相关的激酶活性增加。此外，表达HPV-16 E6的细胞群体显示出有丝分裂纺锤体装配检查点功能降低，并且经历化学诱导的S期过早有丝分裂的趋势增加。具有降低的靶向p53降解能力的HPV-16 E6突变体不能消除有丝分裂检查点，显性阴性p53突变体基因的表达也使有丝分裂检查点功能降低，表明HPV-16 E6部分地通过失活p53来破坏有丝分裂检查点。除有丝分裂检查点破坏外，HPV编码的活性还干扰细胞凋亡信号转导途径。凋亡既是宿主抗病毒防御的重要组成部分，又可以抑制肿瘤发生。 HPV-16 E7癌蛋白抑制由抗病毒细胞因子，肿瘤坏死因子-启动的凋亡信号转导。

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  • 作者

    Thompson, David Alan.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Cellular biology.;Oncology.;Molecular biology.
  • 学位 Ph.D.
  • 年度 1998
  • 页码 290 p.
  • 总页数 290
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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