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首页> 外文学位 >Analyses of alternative splicing and deletion mutants identify an inhibitory domain in human transcription factor REL, an oncogenic member of the NF-kappaB family of proteins.
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Analyses of alternative splicing and deletion mutants identify an inhibitory domain in human transcription factor REL, an oncogenic member of the NF-kappaB family of proteins.

机译：选择性剪接和缺失突变体的分析确定了人类转录因子REL（NF-κB蛋白家族的致癌成员）中的抑制域。

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摘要

The NF-kappaB family of transcription factors is involved in the regulation of many normal cellular processes including inflammation, immune response, and cell growth and survival. Additionally, NF-kappaB has been implicated in many human diseases, including heart disease, chronic inflammation, neurodegenerative disorders, and cancer.;Misregulation of REL, an NF-kappaB transcription factor, has been described in several human lymphoid malignancies. Genetic alterations in REL have been found in human B-cell lymphomas in the form of amplifications, C-terminal deletions, and point mutations. Moreover, overexpression of REL can malignantly transform chicken lymphoid cells. These findings implicate REL in human oncogenesis, and thus, the goal of this research is to further characterize REL functional domains so as to further understand how REL contributes to lymphoid malignancy.;REL has a conserved N-terminal DNA-binding/dimerization domain called the Rel homology domain (RHD) and a C-terminal transactivation domain (TAD). Herein, residues (amino acids [aa] 323-422) between the RHD and TAD are defined as a REL inhibitory domain (RID) because deletion of these sequences increases both REL transactivation and DNA binding. Furthermore, two REL mRNA splice variants that encode proteins with alterations near RID are characterized: one lacking exon 9 sequences (aa 308-330; RELDelta9) and one with an exonized Alu fragment (REL+Alu). Deletion of RID or exon 9-encoded residues increases three activities of REL: transactivation by GAL4-REL, transactivation by full-length REL from certain kappaB site-containing promoters, and DNA binding by REL. Deletion of RID does not affect REL's ability to transform chicken spleen cells. RT-PCR analysis indicates that the RELDelta9 splice variant is preferentially expressed in lymphoma cell lines and primary DLBCLs, suggesting that the REL transcript lacking exon 9 could serve as a marker for certain types of lymphoid tumors. A two-hybrid screen identifies RanBPM as a protein that can specifically interact with exon 9-encoded residues. In addition, the interaction of REL with the coactivator p300 is investigated. A comprehensive analysis of mRNAs encoding NF-kappaB signaling pathway proteins reveals that many NF-kappaB signaling components undergo alternative splicing. Several of these splice variants can alter normal NF-kappaB signaling and may play a role in NF-kappaB-associated diseases.
机译：NF-κB转录因子家族参与许多正常细胞过程的调节，包括炎症，免疫反应以及细胞生长和存活。此外，NF-kappaB与许多人类疾病有关，包括心脏病，慢性炎症，神经退行性疾病和癌症。NF-kappaB转录因子REL的失调在几种人类淋巴恶性肿瘤中都有描述。已经在人类B细胞淋巴瘤中发现REL中的遗传改变，其形式为扩增，C端缺失和点突变。而且，REL的过表达可以恶性转化鸡淋巴样细胞。这些发现暗示了REL在人类肿瘤发生中的作用，因此，本研究的目的是进一步表征REL的功能结构域，以便进一步了解REL如何促进淋巴样恶性肿瘤。REL具有保守的N末端DNA结合/二聚结构域，称为Rel同源域（RHD）和C末端反式激活域（TAD）。在本文中，RHD和TAD之间的残基（氨基酸[aa] 323-422）被定义为REL抑制域（RID），因为这些序列的缺失增加了REL反式激活和DNA结合。此外，表征了两个REL mRNA剪接变体，它们编码在RID附近有变化的蛋白质：一个缺少外显子9序列（aa 308-330； RELDelta9），另一个缺少外显子Alu片段（REL + Alu）。删除RID或外显子9编码的残基会增加REL的三种活性：通过GAL4-REL进行反式激活，通过全长REL从某些含kappaB位点的启动子进行反式激活以及通过REL进行DNA结合。删除RID不会影响REL转化鸡脾细胞的能力。 RT-PCR分析表明，RELDelta9剪接变体在淋巴瘤细胞系和原发性DLBCLs中优先表达，这表明缺少外显子9的REL转录本可以作为某些类型的淋巴瘤的标志物。两种杂交筛选将RanBPM鉴定为可以与外显子9编码的残基特异性相互作用的蛋白质。另外，研究了REL与共激活因子p300的相互作用。对编码NF-kappaB信号通路蛋白的mRNA的全面分析显示，许多NF-kappaB信号传导成分都经过可变剪接。这些剪接变体中的几种可以改变正常的NF-κB信号传导，并可能在与NF-κB相关的疾病中起作用。

著录项

  • 作者

    Leeman, Joshua R.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 273 p.
  • 总页数 273
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;
  • 关键词

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