Differential regulation of RNA processing by Akt isoforms

Akt 亚型对 RNA 加工的差异调节

基本信息

  • 批准号:
    8889119
  • 负责人:
  • 金额:
    $ 37.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-15 至 2020-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): A phosphoproteomics screen in a set of isogenic lung fibroblast cell lines expressing different Akt isoforms, identified 606 Akt target proteins. Ingenuity pathway network function analysis of the data identified a host of network functions that appear to be differentially regulated by the three isoforms. One of these functions is RNA processing, which was represented by 25 proteins that operate at different stages of RNA biogenesis and are phosphorylated by at least one of the three isoforms. The main focus of this work is on one of these proteins (IWS1), which plays a critical role in the assembly of a transcriptional elongation complex on the C- terminal domain (CTD) of the large subunit of RNA polymerase II. Based on studies we recently published (Sanidas et al Mol Cell 53: 577, 2014), we now know that IWS1 is phosphorylated by Akt3 and Akt1, but not Akt2 at the conserved Ser720/Thr721 site. More important, IWS1 phosphorylation at this site is required for the recruitment of the histone H3 K36 trimethyltransferase SetD2 to the IWS1-dependent transcriptional elongation complex. The inhibition of IWS1 phosphorylation, prevents the recruitment of SetD2 and the trimethylation of histone H3 at K36 in the body of target genes during transcription. This abrogates the recruitment of the histone H3K36me3-interacting protein MRG15 and its binding partner polypyrimidine tract binding protein (PTB) and results in shifts in alternative splicing of target genes, one of which is FGFR-2. Alternative splicing gives rise to two FGFR-2 isoforms, IIIb and IIIc, which are expressed in epithelial and mesenchymal cells respectively and of which only the IIIc isoform encodes a receptor that is recognized by FGF-2. In cancer cells, the switch from IIIb to IIIc is associated with EMT and increased cell motility an invasiveness. The phosphorylation of IWS1 by Akt3 and Akt1 promotes a shift from the IIIb to the IIIc isoform and stimulates the proliferation, migration, invasiveness and oncogenic potential of human tumor cell lines. Some, although not all, of these effects of IWS1 phosphorylation can be fully explained by the alternative splicing of FGFR-2. The role of IWS1 phosphorylation in primary human non-small cell lung carcinomas (NSCLCs), was determined by analyzing the expression and phosphorylation of IWS1 in a set of 24 primary NSCLCs. Twenty one of the 24 NSCLCs were found to express IWS1. More important, the stoichiometry of IWS1 phosphorylation in these tumors was fond to correlate with the FGFR-2 splicing pattern and with Akt phosphorylation and Akt3 expression. These data identify an Akt isoform-dependent regulatory mechanism for RNA processing and demonstrate its role in lung cancer. Our plan is to take advantage of the window to the poorly understood regulation of RNA splicing that is opened by these data, to explore the role of Akt in alternative splicing in normal and tumor cells.


项目成果

期刊论文数量(0)
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PHILIP N. TSICHLIS其他文献

PHILIP N. TSICHLIS的其他文献

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{{ truncateString('PHILIP N. TSICHLIS', 18)}}的其他基金

Differential regulation of RNA processing by Akt isoforms
Akt 亚型对 RNA 加工的差异调节
  • 批准号:
    9054812
  • 财政年份:
    2015
  • 资助金额:
    $ 37.74万
  • 项目类别:
Tpl2 in Intestinal Tumorigenesis
Tpl2 在肠道肿瘤发生中的作用
  • 批准号:
    8090464
  • 财政年份:
    2010
  • 资助金额:
    $ 37.74万
  • 项目类别:
Tpl2 in Intestinal Tumorigenesis
Tpl2 在肠道肿瘤发生中的作用
  • 批准号:
    7785303
  • 财政年份:
    2010
  • 资助金额:
    $ 37.74万
  • 项目类别:
Tpl2 in Intestinal Tumorigenesis
Tpl2 在肠道肿瘤发生中的作用
  • 批准号:
    8455709
  • 财政年份:
    2010
  • 资助金额:
    $ 37.74万
  • 项目类别:
Tpl2 in Intestinal Tumorigenesis
Tpl2 在肠道肿瘤发生中的作用
  • 批准号:
    8252225
  • 财政年份:
    2010
  • 资助金额:
    $ 37.74万
  • 项目类别:
Regulation of the Tp12 Kinase
Tp12 激酶的调节
  • 批准号:
    7559001
  • 财政年份:
    2005
  • 资助金额:
    $ 37.74万
  • 项目类别:
Regulation of the Tp12 Kinase
Tp12 激酶的调节
  • 批准号:
    7189344
  • 财政年份:
    2005
  • 资助金额:
    $ 37.74万
  • 项目类别:
Regulation of the Tp12 Kinase
Tp12 激酶的调节
  • 批准号:
    7028286
  • 财政年份:
    2005
  • 资助金额:
    $ 37.74万
  • 项目类别:
Regulation of the Tp12 Kinase
Tp12 激酶的调节
  • 批准号:
    6886332
  • 财政年份:
    2005
  • 资助金额:
    $ 37.74万
  • 项目类别:
Regulation of the Tp12 Kinase
Tp12 激酶的调节
  • 批准号:
    7350941
  • 财政年份:
    2005
  • 资助金额:
    $ 37.74万
  • 项目类别:

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