Stress Response Functions of ADAR1 Regulated by MAP Kinases

MAP 激酶调控 ADAR1 的应激反应功能

基本信息

  • 批准号:
    10330572
  • 负责人:
  • 金额:
    $ 37.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-02-01 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY RNA editing that converts adenosine to inosine (A-to-I RNA editing) specifically in double-stranded RNAs (dsRNAs) is catalyzed by adenosine deaminases acting on RNA (ADARs). We pioneered in the field of A-to-I RNA editing by identifying the first ADAR gene family member, ADAR1. Although ADAR1 edits select protein coding sequences, its most common targets are non-coding sequences consisting of inverted repeats of retrotransposon elements such as Alu and SINE. There are two ADAR1 isoforms, one, mainly nuclear localized ADAR1p110, and the other, mostly cytoplasmic ADAR1p150. Furthermore, it seems that there are RNA editing-dependent and -independent functions of ADAR1. We recently discovered a new RNA editing-independent function of ADAR1. Stress-induced phosphorylation of three threonines and two serines of ADAR1 by MKK6-p38-MSK1/2 MAP kinases increased the binding affinity of ADAR1p110 to Exportin-5 (Xpo5) and its nuclear export mediated by the Xpo5/RanGTP system. Once translocated to the cytoplasm, ADAR1p110 promoted survival of stressed cells by protecting anti-apoptotic gene transcripts carrying 3'UTR Alu dsRNA from Staufen1/UPF1-mediated mRNA decay (SMD). In this application, we will explore this newly found stress response function of ADAR1. Using a Luciferase expression construct carrying 3'UTR streptavidin-binding RNA aptamers and Alu-dsRNA structure, we will identify the ribonuclease that degrades the stress response SMD target mRNAs, which are otherwise protected by ADAR1. We will characterize the ribonuclease activity and its role in the stress induced SMD mechanism. We will then identify “cargo” dsRNAs, which are exported to the cytoplasm together with the phosphorylated ADAR1p110 by a sequential affinity chromatography using differentially epitope-tagged Xpo5, RanQ96L, and phosphomimetic ADAR1p110 expression constructs. We will determine the function of the dsRNAs in the stress response mechanism by their ectopic expression and knock down experiments. ADAR1 null embryos die at E11-12 due to widespread apoptosis. Using antibodies specific to the ADAR1 phosphorylated at T808, T811, S814, S823, and S825, we will determine when and where the stress induced ADAR1 phosphorylation occurs during embryonic development. We will then create and conduct phenotypic analysis of new ADAR1 knockin mutant mouse lines, ADAR1-T/S-to-A and ADAR1-T/S-to-D. ADAR1-T/S-to-A mice express solely ADAR1-T/S-to-A non-phosphorylatable mutant proteins, whereas ADAR1-T/S-to-D mice express solely phosphomimetic ADAR1 proteins. By comparing phenotypic differences among these new mutant mouse strains, we will evaluate the importance of the ADAR1 stress response function during embryo development and in adult life. Apoptosis of stressed and DNA-damaged cells is one way to prevent their transformation to cancers, and, thus, the stress response function of ADAR1 is very likely to be relevant to oncogenic transformation process.
项目总结

项目成果

期刊论文数量(0)
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KAZUKO NISHIKURA其他文献

KAZUKO NISHIKURA的其他文献

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{{ truncateString('KAZUKO NISHIKURA', 18)}}的其他基金

Stress Response Functions of ADAR1 Regulated by MAP Kinases
MAP 激酶调控 ADAR1 的应激反应功能
  • 批准号:
    10093094
  • 财政年份:
    2019
  • 资助金额:
    $ 37.51万
  • 项目类别:
Control of Breast Cancer Metastasis by Epstein-Barr Virus microRNA
EB 病毒 microRNA 控制乳腺癌转移
  • 批准号:
    8625434
  • 财政年份:
    2014
  • 资助金额:
    $ 37.51万
  • 项目类别:
Control of Breast Cancer Metastasis by Epstein-Barr Virus microRNA
EB 病毒 microRNA 控制乳腺癌转移
  • 批准号:
    9187428
  • 财政年份:
    2014
  • 资助金额:
    $ 37.51万
  • 项目类别:
Control of Cardiogenesis by microRNA Editing
通过 microRNA 编辑控制心脏发生
  • 批准号:
    7934485
  • 财政年份:
    2009
  • 资助金额:
    $ 37.51万
  • 项目类别:
Control of Cardiogenesis by microRNA Editing
通过 microRNA 编辑控制心脏发生
  • 批准号:
    7810127
  • 财政年份:
    2009
  • 资助金额:
    $ 37.51万
  • 项目类别:
Characterization of TRBP-containing complexes
含TRBP复合物的表征
  • 批准号:
    7146839
  • 财政年份:
    2006
  • 资助金额:
    $ 37.51万
  • 项目类别:
Functions of ADARI RNA Editase in Erythropoiesis
ADARI RNA 编辑酶在红细胞生成中的功能
  • 批准号:
    6746917
  • 财政年份:
    2002
  • 资助金额:
    $ 37.51万
  • 项目类别:
Functions of ADARI RNA Editase in Erythropoiesis
ADARI RNA 编辑酶在红细胞生成中的功能
  • 批准号:
    6465404
  • 财政年份:
    2002
  • 资助金额:
    $ 37.51万
  • 项目类别:
Functions of ADARI RNA Editase in Erythropoiesis
ADARI RNA 编辑酶在红细胞生成中的功能
  • 批准号:
    6833858
  • 财政年份:
    2002
  • 资助金额:
    $ 37.51万
  • 项目类别:
Functions of ADARI RNA Editase in Erythropoiesis
ADARI RNA 编辑酶在红细胞生成中的功能
  • 批准号:
    6912766
  • 财政年份:
    2002
  • 资助金额:
    $ 37.51万
  • 项目类别:

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