Single Cell Analysis of Cross Talk Among Kinase Pathways
激酶通路间串扰的单细胞分析
基本信息
- 批准号:7324436
- 负责人:
- 金额:$ 5.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-01-01 至 2008-12-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 4-Kinase3T3 CellsActivation AnalysisAddressAllelesAnchorage-Independent GrowthApoptoticBehaviorBiochemicalBiochemical PhenomenaBiological AssayBiological ModelsBiological ProcessCancer BiologyCell CycleCell LineCell SurvivalCellsCharacteristicsCloningComplexDNA Sequence RearrangementDataDevelopmentDrug DesignExcisionGTP-Binding ProteinsHumanHuman Cell LineIndividualInvestigationKineticsLasersLifeMAP Kinase ModulesMaintenanceMalignant - descriptorMalignant NeoplasmsMeasurementMeasuresMethodsMitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesModelingMonitorMusMutateNIH 3T3 CellsOncogene ProteinsOncogenesOncogenicPathway interactionsPeptidesPhenotypePhosphatidylinositolsPhosphotransferasesPlayPopulationPropertyProtein-Serine-Threonine KinasesProtocols documentationRangeRelative (related person)ReporterRodentRoleSeriesSignal PathwaySignal TransductionSignal Transduction PathwaySignaling ProteinStimulation of Cell ProliferationStimulusSystemTechniquesTechnologyTestingTimeTumor Cell LineWithdrawalcell behaviorcomparativeextracellularfibrosarcomagenetic regulatory proteinneoplastic cellp21 N-Ras Proteinp21 activated kinaseras Oncogeneresearch studyresponsesingle cell analysistime intervaltumor growthtumor progressiontumorigenesistumorigenic
项目摘要
Interactingcascadesof signaling proteins, particularly kinases, play crucial roles in the development and maintenance of cancer.
Despite their importance inoncogenic signal transduction pathways, little is understood about the biochemical behavior of these
)roteinswithin the context of the living cell. It is now clear that these signaling cascades are not merely a linear series of enzymatic
¿eactions leadingfrom discrete stimuli to defined cellular responses. Rather, they are interrelated in complex networks such that their
biochemical propertieswithin the living cell are not intuitive. Traditional biochemical studies that rely on lysates of bulk cell
populationscannot decipher the inherent properties of cell signaling due to averaging of heterogeneous cellular responses across the
population. To understandsuch biochemical phenomena as cross-talk between pathways, thresholds of activation and bistable
states, kinaseassays must be performed in intact, single cells. The currentwork is directed at decoding the biochemical behaviors of
the Ras-related pathways- signaling pathways of particular importto cancer biology. These studies will apply a powerful new
technologyfor kinase assays in single cells to a unique series of tumor cell lines possessing contitutively active or inactive signaling
proteins. The cell lines (human HT1080/MCH603 fibrosarcomaand mouse NIH3T3) display a range of tumorigenic characteristics
dependent on the repertoire of constitutive activity in Ras-relatedSignalingpathways. In mass populations of MCH603 cells our data
support the notion that the threshold behavior and crosstalk among these pathways closely relate to the relative aggressiveness of
their tumorigenic phenotype. The current studies will reveal how the behavior of signaling cascades involving the kinases
phosphoinositide-3-kinase (P13K), Akt, p21-activated kinase and Erkl/2 interrelate in living, single cells. The specific aims for this
project are to 1) determinewhether induction of crosstalk, generated by P13K activity, requires a threshold level of activated P13K; 2
determine if cross-activation of these kinase pathways is coordinate or sequential; and 3) determine if cross-talk activation of MAP
kinase cascades is reversible or irreversible after withdrawal of the P13K or Akt stimulus. These studies will provide additional
information relating to our understanding of the consequencesof activationof kinase signaling pathwayswith respect to malignant
transformation, aggressive tumor growth and survival.
信号蛋白的相互作用,特别是激酶,在癌症的发展和维持中起着至关重要的作用。
尽管它们在致癌信号转导通路中很重要,但对它们的生化行为知之甚少。
)roteins在活细胞的上下文中。现在很清楚,这些信号级联不仅仅是一系列线性的酶促反应,
从离散的刺激到确定的细胞反应。相反,它们在复杂的网络中相互关联,
活细胞内的生物化学性质不是直观的。传统的生物化学研究依赖于大量细胞的裂解物
人群不能破译细胞信号传导的固有特性,这是由于整个人群中异质细胞反应的平均化,
人口理解诸如通路之间的串扰、激活阈值和激活阈值等生物化学现象。
因此,kinaseassays必须在完整的单细胞中进行。目前的工作是针对解码的生化行为,
Ras相关通路--对癌症生物学特别重要的信号通路。这些研究将应用一个强大的新的
一种在单细胞中对具有结构性活性或非活性信号传导的独特系列肿瘤细胞系进行激酶测定的技术
proteins.细胞系(人HT 1080/MCH 603纤维肉瘤和小鼠NIH 3 T3)显示出一系列致瘤特性
依赖于Ras相关信号通路的组成性活性库。在大量的MCH 603细胞群体中,我们的数据
支持这样的观点,即这些通路之间的阈值行为和串扰与
它们的致瘤表型。目前的研究将揭示涉及激酶的信号级联的行为
磷酸肌醇-3-激酶(P13 K)、Akt、p21激活的激酶和Erkl/2在活的单细胞中相互关联。具体目标是
项目是1)确定由P13 K活性产生的串扰的诱导是否需要激活的P13 K的阈值水平; 2
确定这些激酶途径的交叉激活是协调的还是顺序的;以及3)确定MAP的交叉激活是否
取消P13 K或Akt刺激后,激酶级联反应是可逆或不可逆的。这些研究将提供更多
与我们理解激酶信号通路激活对恶性肿瘤的影响有关的信息,
转化、侵袭性肿瘤生长和存活。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ERIC J. STANBRIDGE', 18)}}的其他基金
Single Cell Analysis of Cross Talk Among Kinase Pathways
激酶通路间串扰的单细胞分析
- 批准号:
7178789 - 财政年份:2005
- 资助金额:
$ 5.39万 - 项目类别:
Single Cell Analysis of Cross Talk Among Kinase Pathways
激酶通路间串扰的单细胞分析
- 批准号:
6872729 - 财政年份:2005
- 资助金额:
$ 5.39万 - 项目类别:
Single Cell Analysis of Cross Talk Among Kinase Pathways
激酶通路间串扰的单细胞分析
- 批准号:
7055189 - 财政年份:2005
- 资助金额:
$ 5.39万 - 项目类别:
Single Cell Analysis of Cross Talk Among Kinase Pathways
激酶通路间串扰的单细胞分析
- 批准号:
6999728 - 财政年份:2005
- 资助金额:
$ 5.39万 - 项目类别:
DOMINANT-NEGATIVE AND GAIN OF FUNCTION P53 MUTATIONS
P53 显性失活和功能获得突变
- 批准号:
6164194 - 财政年份:1996
- 资助金额:
$ 5.39万 - 项目类别:
DOMINANT-NEGATIVE AND GAIN OF FUNCTION P53 MUTATIONS
P53 显性失活和功能获得突变
- 批准号:
2882426 - 财政年份:1996
- 资助金额:
$ 5.39万 - 项目类别:
EVALUATION OF DOMINANTLY-ACTING RAS ONCOGENES
对起主导作用的 RAS 癌基因的评估
- 批准号:
2668028 - 财政年份:1996
- 资助金额:
$ 5.39万 - 项目类别:
DOMINANT-NEGATIVE AND GAIN OF FUNCTION P53 MUTATIONS
P53 显性失活和功能获得突变
- 批准号:
2376977 - 财政年份:1996
- 资助金额:
$ 5.39万 - 项目类别:
EVALUATION OF DOMINANTLY-ACTING RAS ONCOGENES
对起主导作用的 RAS 癌基因的评估
- 批准号:
2113574 - 财政年份:1996
- 资助金额:
$ 5.39万 - 项目类别:
EVALUATION OF DOMINANTLY-ACTING RAS ONCOGENES
对起主导作用的 RAS 癌基因的评估
- 批准号:
6459503 - 财政年份:1996
- 资助金额:
$ 5.39万 - 项目类别:
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