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首页> 外文学位 >Adenovirus E1A 12S-induced changes during immortalization and transformation of primary epithelial cells.
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Adenovirus E1A 12S-induced changes during immortalization and transformation of primary epithelial cells.

机译：腺病毒E1A 12S诱导的原代上皮细胞永生化和转化过程中的变化。

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摘要

The Adenovirus E1A 12S oncoprotein can immortalize and cooperate with other oncoproteins to transform primary epithelial cells. First exon functions are required for transient activation of quiescent cells into the cell cycle, whereas second exon functions are necessary for maintenance of proliferation and escape from senescence, leading to immortalization. The various functions of E1A 12S are mediated by its association with several cellular proteins including the pRB family of proteins and p300.;The importance of E1A protein complexes in immortalization was analyzed. The immortalization-defective second exon mutant proteins associate with p300 and pRB as efficiently as the immortalization-competent and wild type 12S protein. The second exon mutants also retain the ability to phosphorylate pRB and induce early cellular DNA synthesis. However, the immortalization-defective mutants are unable to reinduce cellular DNA synthesis at a later stage during immortalization, unlike the wild type 12S virus. Immortalization by E1A 12S, therefore, involves functions associated with early and late events that are encoded by the two exons of 12S.;Immortalization requires expression of both exons of 12S, whereas the second exon is dispensable for cotransformation with activated ras, suggesting an interaction between the second exon-encoded functions of 12S and the ras signal transduction pathway. Consistent with this, wild type 12S induces the formation of a complex between GTPase-activating protein (GAP) and a novel 110 kD cellular protein, p110. An amino terminal region, encoded by nucleotides 560-598, and a carboxy terminal region, encompassed by nucleotides 1437-1542 of 12S, are required for this induction. The two regions cooperate, in trans, to induce the p110-GAP complex. These same regions are also required for immortalization, suggesting that the 12S-induced p110-GAP complex may play a role in immortalization.;Cotransformation with activated ras requires only the first exon functions of 12S, however, second exon mutants cooperate more efficiently with activated ras to generate hypertransformed cells that no longer exhibit cell-cell interactions. Wild type transformed cells express and localize E-cadherin to the intercellular junctions, whereas hypertransformed cells express E-cadherin, but fail to localize it to the cell-cell junctions. Expression of wild type 12S in such hypertransformed cells results in reformation of cell junctions and appropriate localization of E-cadherin. Thus, wild type 12S suppresses the hypertransformation phenotype and functions to maintain the differentiated characteristics of epithelial cells.
机译：腺病毒E1A 12S癌蛋白可以永生并与其他癌蛋白协同作用以转化原代上皮细胞。第一外显子功能是使静止细胞瞬时激活进入细胞周期所必需的，而第二外显子功能对于维持增殖和逃避衰老，导致永生化是必需的。 E1A 12S的各种功能是通过与多种细胞蛋白（包括pRB家族蛋白和p300）的结合而介导的。分析了E1A蛋白复合物在永生化中的重要性。具有永生化缺陷的第二外显子突变蛋白与具有永生化能力的野生型12S蛋白一样有效地与p300和pRB缔合。第二个外显子突变体还保留了磷酸化pRB并诱导早期细胞DNA合成的能力。但是，与野生型12S病毒不同，永生化缺陷型突变体无法在永生化的后期阶段重新诱导细胞DNA合成。因此，E1A 12S的永生化涉及与12S的两个外显子编码的早期和晚期事件相关的功能;不朽化需要12S的两个外显子都表达，而第二个外显子对于与活化的ras共转化是必不可少的，表明存在相互作用在12S的第二个外显子编码功能与ras信号转导途径之间与此相一致，野生型12S诱导GTPase激活蛋白（GAP）和新型110 kD细胞蛋白p110之间形成复合物。该诱导需要由核苷酸560-598编码的氨基末端区域和由12S的核苷酸1437-1542包围的羧基末端区域。这两个区域反过来合作以诱导p110-GAP复合物。永生化也需要这些相同的区域，这表明12S诱导的p110-GAP复合体可能在永生化中起作用。;与活化的ras共转化仅需要12S的第一个外显子功能，但是，第二个外显子突变体与活化的s合作更有效ras生成不再显示细胞间相互作用的超转化细胞。野生型转化细胞表达E-钙粘蛋白并将其定位在细胞间连接处，而超转化细胞表达E-钙粘蛋白，但无法将其定位在细胞-细胞连接处。在这种超转化细胞中野生型12S的表达导致细胞连接的重构和E-钙粘着蛋白的适当定位。因此，野生型12S抑制了超转化表型并起到维持上皮细胞分化特征的作用。

著录项

  • 作者

    Gopalakrishnan, Shobha.;

  • 作者单位

    The University of Tennessee Health Science Center.;

  • 授予单位 The University of Tennessee Health Science Center.;
  • 学科 Biology Microbiology.;Biology Cell.;Health Sciences Oncology.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 1996
  • 页码 220 p.
  • 总页数 220
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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