How do Tumor Cells Gain Anchorage Independency?

肿瘤细胞如何获得贴壁独立性?

基本信息

  • 批准号:
    8204485
  • 负责人:
  • 金额:
    $ 35.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-02-05 至 2013-12-31
  • 项目状态:
    已结题

项目摘要

Abstract The transforming proteins of DNA tumor viruses interact with endogenous cellular factors that can play broad roles in the regulation of cell growth. The best-characterized example of an endogenous cell cycle regulator protein that interacts with a DNA virus transforming protein is pRB. However, there are other examples. A very high molecular weight (600 kDa) cellular protein (hereafter termed "p600") forms a tight protein:protein complex with the E7 transforming factor of human and bovine papillomaviruses (HPV). In preliminary studies, my collaborators and I have shown that p600 plays a generalized role in anchorage independent growth and malignant transformation of many tumor cell types. The broad objective of work proposed here is to understand anchorage dependency and malignant transformation through purification and enzymatic characterization of E7-displacible, p600 binding proteins. I have two specific aims: Aim 1 is to identify cellular factors that bind to p600 in an E7-dependent fashion. The p600 protein is too large for genetic manipulation or ectopic expression using conventional approaches. In preliminary studies, I have used a "knock in" strategy to create ES cells that express tandem affinity epitope-tagged p600. In antibody pull down experiments with these cells, I have several p600- binding cellular proteins that are displaced by HPV E7. The study plan for aim 1 describes how I will purify and identify these E7-displacible factors using biochemical protocols and mass spectroscopy. Aim 2 is to understand how E7 and E7-displacible cellular proteins might regulate p600 transforming functions. In preliminary studies, I have shown that p600 has ubiquitin ligase activity. I hypothesize that the ubuquitin ligase activity of p600 is regulated by interactions with E7 and E7-displacibile cellular factors. To test this hypothesis, I will characterize the ubiquitin ligase domain of p600 and identify E7-specific ubiquitin ligase substrates. In proof-of-concept studies for these two specific aims, I have already identified one p600-binding, E7-displacible protein as PKM2 - a protein kinase that has recently been shown to play a broad role in anabolic growth of tumors. I believe that these experiments will provide new insights into the molecular mechanisms of the malignant phenotype including anoikis and anchorage-dependent growth. In the fullness of time, the work could lead to novel new targets for anti cancer drug development.
摘要

项目成果

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YOSHIHIRO NAKATANI其他文献

YOSHIHIRO NAKATANI的其他文献

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{{ truncateString('YOSHIHIRO NAKATANI', 18)}}的其他基金

How do Tumor Cells Gain Anchorage Independency?
肿瘤细胞如何获得贴壁独立性?
  • 批准号:
    7887339
  • 财政年份:
    2010
  • 资助金额:
    $ 35.22万
  • 项目类别:
How do Tumor Cells Gain Anchorage Independency?
肿瘤细胞如何获得贴壁独立性?
  • 批准号:
    8022878
  • 财政年份:
    2010
  • 资助金额:
    $ 35.22万
  • 项目类别:
How do Tumor Cells Gain Anchorage Independency?
肿瘤细胞如何获得贴壁独立性?
  • 批准号:
    8408805
  • 财政年份:
    2010
  • 资助金额:
    $ 35.22万
  • 项目类别:
Druggable Mechanisms
药物机制
  • 批准号:
    8322137
  • 财政年份:
    2004
  • 资助金额:
    $ 35.22万
  • 项目类别:
Druggable Mechanisms
药物机制
  • 批准号:
    8380641
  • 财政年份:
    2004
  • 资助金额:
    $ 35.22万
  • 项目类别:
Druggable Mechanisms
药物机制
  • 批准号:
    7756535
  • 财政年份:
    2004
  • 资助金额:
    $ 35.22万
  • 项目类别:
Druggable Mechanisms
药物机制
  • 批准号:
    8133125
  • 财政年份:
    2004
  • 资助金额:
    $ 35.22万
  • 项目类别:
Druggable Mechanisms
药物机制
  • 批准号:
    8532051
  • 财政年份:
    2004
  • 资助金额:
    $ 35.22万
  • 项目类别:
Transcriptional Regulation by Chromatin Modifiers
染色质修饰剂的转录调控
  • 批准号:
    6513785
  • 财政年份:
    2002
  • 资助金额:
    $ 35.22万
  • 项目类别:
Transcriptional Regulation by Chromatin Modifiers
染色质修饰剂的转录调控
  • 批准号:
    6760038
  • 财政年份:
    2002
  • 资助金额:
    $ 35.22万
  • 项目类别:

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