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首页> 外文学位 >The HTLV-1 oncoprotein Tax and the tumor suppressorp53 bind a common domain of CBP/p300 to mediate transcriptional activation.
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The HTLV-1 oncoprotein Tax and the tumor suppressorp53 bind a common domain of CBP/p300 to mediate transcriptional activation.

机译：HTLV-1癌蛋白Tax和肿瘤抑制因子p53结合CBP / p300的共同结构域来介导转录激活。

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摘要

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent associated with the development of adult T-cell leukemia and encodes a viral transactivator known as Tax. While the precise molecular mechanism by which cellular transformation occurs is unknown, researchers hypothesize that Tax is essential in both viral and cellular gene expression. To activate HTLV-1 transcription, Tax interacts with the cellular protein CREB, and the pleiotropic coactivators CBP/p300. We have characterized a novel and potentially important alternate binding site for Tax on the carboxy-terminal region of CBP/p300 that mediates Tax transcription function. We have determined the minimal binding domain for Tax at the carboxy-terminal binding region, termed CR2, as amino acids 2003 to 2212. A double point mutant of CR2 directed to one of the α-helical motifs in this domain was found to be defective for binding to Tax. We also characterize the region of Tax responsible for interaction with CR2 and show that the previously identified transactivation domain of Tax (amino acids 312 to 319) participates in CR2 binding.;The tumor suppressor p53 also recruits the cellular coactivator CBP/p300 to mediate the transcriptional activation of target genes. Previously, p53 has been shown to interact with several regions of CBP/p300, including the C/H3 and KIX domains. We find that p53 also interacts strongly with a smaller region of the CR2 domain encompassing amino acids 2055 to 2150. We show that the same double point mutation targeted to the first α-helical motif in this domain, defective for interaction with Tax, is also compromised for interaction with p53. The observation that both p53 and Tax bind to overlapping regions of CR2 led us to ask whether or not their binding is mutually exclusive. We show that p53 and Tax compete for binding CR2. Thus, Tax disruption of the p53-CR2 complex may be a contributing molecular event in the HTLV-1 transformation pathway. Together, these studies identify novel Tax-interacting and p53interacting sites on CBP/p300 and extend our understanding of the molecular mechanism of Tax transactivation.
机译：1型人T细胞白血病病毒（HTLV-1）是与成人T细胞白血病发展相关的病原体，编码一种称为Tax的病毒反式激活因子。尽管尚不清楚发生细胞转化的确切分子机制，但研究人员推测Tax在病毒和细胞基因表达中都是必不可少的。为了激活HTLV-1转录，Tax与细胞蛋白CREB和多效性共激活剂CBP / p300相互作用。我们已经表征了介导Tax转录功能的CBP / p300的羧基末端区域上的Tax的新型和潜在重要的替代结合位点。我们确定了羧基末端结合区的Tax最小结合域（称为CR2），为2003至2212位氨基酸。针对该域中一个α螺旋基序的CR2双点突变被发现是有缺陷的绑定税。我们还表征了负责与CR2相互作用的Tax区域，并表明先前确定的Tax的反式激活结构域（氨基酸312至319）参与了CR2的结合。肿瘤抑制因子p53也募集了细胞共激活因子CBP / p300来介导CR2的结合。靶基因的转录激活。以前，p53已显示与CBP / p300的多个区域相互作用，包括C / H3和KIX域。我们发现p53还与包含氨基酸2055至2150的CR2域的较小区域强烈相互作用。我们显示，针对该域中第一个α-螺旋基序的相同双点突变（与Tax相互作用存在缺陷）也是不能与p53相互作用。 p53和Tax都绑定到CR2的重叠区域的观察使我们问到它们的绑定是否互斥。我们显示p53和Tax竞争结合CR2。因此，p53-CR2复合物的税收破坏可能是HTLV-1转化途径中的一个促成分子事件。总之，这些研究确定了CBP / p300上新的Tax-interact和p53interacting位点，并扩展了我们对Tax transactivation分子机制的理解。

著录项

  • 作者

    Scoggin, Kirsten Elizabeth Strickler.;

  • 作者单位

    Colorado State University.;

  • 授予单位 Colorado State University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 202 p.
  • 总页数 202
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
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