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
- 来源:
- 关键词:AffectAffinityAnchorage-Independent GrowthAnoikisAntibodiesAntineoplastic AgentsApoptosisApoptoticBasic ScienceBindingBinding ProteinsBinding SitesBiochemicalBovine PapillomavirusCarcinomaCell CycleCellsComplexDNA Tumor VirusesDNA VirusesDependencyE2F transcription factorsEctopic ExpressionEpithelial CellsEpitopesExtracellular MatrixGrowthHumanHuman PapillomavirusImmuneKnock-in MouseLarge T AntigenLeadLigaseMG132Malignant - descriptorMalignant Epithelial CellMass Spectrum AnalysisMolecularMolecular WeightNeoplasm MetastasisPathway interactionsPlayProteasome InhibitorProtein BindingProtein KinaseProteinsProtocols documentationRegulationResearchRetinoblastoma ProteinRoleSignal TransductionSimian virus 40StagingTestingViralWorkabstractingcell growth regulationcell motilitycell typedrug developmentdrug discoveryembryonic stem cellgenetic manipulationindependencyinsightkillingsmalignant phenotypeneoplastic cellnovelprotein complexprotein degradationresearch studyresponsetumor growthtumorigenesisubiquitin ligase
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:
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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