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首页> 外文学位 >Cancer, cell fate, and transcription: Regulation of the p53 transcriptional response by structurally diverse core promoters.
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Cancer, cell fate, and transcription: Regulation of the p53 transcriptional response by structurally diverse core promoters.

机译：癌症，细胞命运和转录：通过结构多样的核心启动子调节p53转录反应。

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摘要

The aim of my dissertation research was to understand the mechanisms underlying the transcriptional response to stress by the tumor suppressor protein p53 and and their influence on cell fate decisions. This was accomplished by several complementary experimental approaches that compared two p53-mediated transcriptional programs, cell cycle arrest and apoptosis. Since p53 is central to the cellular response to stress signals, it is important to define the events that are involved during p53 activation of cell cycle arrest and pro-apoptotic genes. p53 target promoters are structurally diverse and display pronounced differences in RNA polymerase II (RNAP II) occupancy even in unstressed cells, with higher levels observed on cell cycle arrest genes (p21) compared to apoptotic genes (Fas/APO1). This occupancy correlates well with their ability to undergo rapid or delayed stress-induction. To understand the basis for such distinct temporal assembly of transcription complexes, the role of core promoter structures in this process was examined. My studies revealed that the p21 core promoter directs rapid, TATA box dependent assembly of RNAP II pre-initiation complexes (PIC), but permits few rounds of RNAP II re-initiation. By contrast, PIC formation at the Fas/APO1 core promoter is very inefficient but supports multiple rounds of transcription. A downstream element within the Fas/APO1 core promoter is essential for its activation and binds NF-Y. It is known that NF-Y acts as a bi-functional transcription factor that regulates the expression of Fas/APO1 in vivo. Thus, two critical parameters of the stress-induced p53 transcriptional response are the kinetics of gene induction and duration of expression through frequent re-initiation. These features are intrinsic, DNA-encoded properties of diverse core promoters and may be fundamental to anticipatory programming of p53 response genes upon stress.;Analysis of the p21 and Fas/APO1 promoters by in vitro transcription resulted in the identification of three pharmacologic agents that should aid in further dissecting transcriptional mechanisms employed by p53 target genes and other genes regulated by RNAP II. Three kinase inhibitors (hypericin, rottlerin, and Sp600125), previously not associated with inhibiting transcription, were discovered to block transcription initiation efficiently.
机译：本论文研究的目的是了解肿瘤抑制蛋白p53对应激转录应答的潜在机制及其对细胞命运决定的影响。这是通过几种互补的实验方法完成的，该方法比较了两个p53介导的转录程序，细胞周期停滞和凋亡。由于p53对于细胞对应激信号的反应至关重要，因此定义p53激活细胞周期停滞和促凋亡基因所涉及的事件非常重要。 p53靶启动子在结构上是多样的，即使在未受压力的细胞中，RNA聚合酶II（RNAP II）的占用率也存在明显差异，与凋亡基因（Fas / APO1）相比，在细胞周期阻滞基因（p21）上观察到的水平更高。这种占用与他们经历快速或延迟压力诱导的能力密切相关。为了理解转录复合物的这种独特的时间组装的基础，研究了核心启动子结构在该过程中的作用。我的研究表明，p21核心启动子指导快速，依赖TATA盒的RNAP II预起始复合物（PIC）的组装，但允许进行几轮RNAP II重起始。相比之下，在Fas / APO1核心启动子上的PIC形成效率非常低，但支持多轮转录。 Fas / APO1核心启动子中的下游元件对其激活至关重要，并与NF-Y结合。已知NF-Y是在体内调节Fas / APO1表达的双功能转录因子。因此，应激诱导的p53转录反应的两个关键参数是基因诱导的动力学和通过频繁重新启动而表达的持续时间。这些特征是各种核心启动子的内在的，DNA编码的特性，并且可能是应激时预期对p53应答基因进行编程的基础。通过体外转录分析p21和Fas / APO1启动子可以鉴定出三种药物应当进一步剖析p53靶基因和其他受RNAP II调控的基因所采用的转录机制。发现了三种以前与抑制转录无关的激酶抑制剂（hypericin，rottlerin和Sp600125）可以有效地阻止转录起始。

著录项

  • 作者

    Morachis, Jose Manuel.;

  • 作者单位

    University of California, San Diego.;

  • 授予单位 University of California, San Diego.;
  • 学科 Biology Molecular.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 96 p.
  • 总页数 96
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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