Convergence of CREB and MYC Pathways in Oncogenesis.
Convergence of CREB and MYC Pathways in Oncogenesis.
批准号:
9128558
负责人:
Antonio Luigi Amelio
金额:
$24.9万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-09-22 至 2018-08-31
关键词:
Acute Myelocytic LeukemiaAssesAutomobile DrivingB-Cell DevelopmentB-Cell LymphomasB-LymphocytesBindingBreastBronchiC-terminalCREB1 geneCause of DeathCell SurvivalCell divisionCervix UteriCessation of lifeCharacteristicsChromosomal translocationComplexCutaneousCyclic AMP Response ElementDataDevelopmentDimerizationE-Box ElementsEventFamily memberFoundationsGene ActivationGene ExpressionGene TargetingGenesGenetic TranscriptionGenetic studyGoalsHumanIndiumInsulin ReceptorInsulin-Like Growth Factor IInsulin-Like-Growth Factor I ReceptorLinkLungLung AdenocarcinomaLung LymphomaLymphomaLymphomagenesisMLL/ELLMaintenanceMalignant NeoplasmsMammalian CellMediatingMentorsMessenger RNAMetastatic CarcinomaModelingMolecularMusN-terminalNew AgentsOncogenesParentsPathway interactionsPremalignantProcessPromoter RegionsProstate AdenocarcinomaProto-Oncogene Proteins c-mycRecurrenceRegulationResearchResearch Project GrantsResponse ElementsRoleSalivary GlandsSignal TransductionSiteSweat GlandsT-Cell LymphomaTechnologyTestingThyroid GlandTrainingTranscription CoactivatorTranscriptional RegulationTransgenic MiceTumor Suppressor ProteinsUnited Statesautocrinebasecancer preventioncancer therapycell growthcell transformationchromatin immunoprecipitationgenetic approachin vivoinnovationleukemialeukemia/lymphomalung tumorigenesismalignant statemetaplastic cell transformationmouse modelnew technologypromoterreceptorscreeningtooltranscription factortumortumorigenesis
中文摘要
摘要
肿瘤发生是一个复杂的、多基因的过程,导致细胞转化并最终导致
恶性的发展。定义启动和驱动肿瘤发生的分子事件,以及那些
都需要维持恶性状态,仍然是一项艰巨的任务。作为一个发现工具来审问
参与癌症的转录网络,我已经开发、测试和验证了一种创新的哺乳动物
基于细胞的筛选技术,允许人们定义癌基因或肿瘤之间的功能相互作用
参与转录调控的抑制子和蛋白质。这项技术使人们能够整合基因
具有转录因子活性的表达数据,通过定义负责的上游转录调控因子
用来激活基因。在应用这项新技术时,我确定了
癌蛋白CRTC1/MAML2,由重复性t(11;19)(q21;p13.1)染色体产生
将CREB辅活化子CRTC1与缺口辅活化子MAML2和癌基因融合的易位
MYC。此外,我的初步研究强烈表明,CRTC1/MAML2癌蛋白劫持了Myc
推动细胞转化和肿瘤形成的网络。这些发现挑战了现有的范式,即
嵌合癌蛋白表现出仅与其组成的亲本分子有关的功能特征。
鉴于这些发现,我假设CREB和MYC转录因子网络在
致癌作用。使用经过验证的B细胞淋巴瘤模型的遗传学方法将用于测试这一点
假设,在那里我将评估CRTc1/MAML2与MAML2相互作用的相关性并定义机制(S
MYC和CRTCs在驱动细胞转化、淋巴肿大和维持
恶性状态。
英文摘要
ABSTRACT
Tumorigenesis is a complex, multigenic process that leads to cell transformation and ultimately to the
development of malignancy. Defining the molecular events that initiate and drive oncogenesis, and those that
are required to maintain the malignant state, remain a formidable task. As a discovery tool to interrogate
transcriptional networks involved in cancer, I have developed, tested and validated an innovative mammalian
cell-based screening technology that allows one to define functional interactions between oncogenes or tumor
suppressors and proteins implicated in transcriptional control. This technology allows one to integrate gene
expression data with transcription factor activity, by defining the upstream transcriptional regulators responsible
for gene activation. In applying this new technology, I identified a functional interaction between the
oncoprotein CRTC1/MAML2, which is generated by the recurrent t(11;19)(q21;p13.1) chromosomal
translocation that fuses the CREB coactivator CRTC1 to the NOTCH coactivator MAML2, and the oncogene
MYC. Further, my Preliminary Studies strongly suggest that the CRTC1/MAML2 oncoprotein hijacks the Myc
network to drive cell transformation and tumorigenesis. These findings challenge the existing paradigm that
chimeric oncoproteins display functional characteristics related solely to their constituent parent molecules.
Given these findings, I hypothesize that CREB and MYC transcription factor networks cooperate in
oncogenesis. Genetic approaches using validated models of B cell lymphoma will be used to test this
hypothesis, where I will assess the relevance and define the mechanism(s) of CRTC1/MAML2 interactions with
MYC and the role of CRTCs in driving cell transformation, lymphomagenesis, and the maintenance of the
malignant state.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.ccell.2015.05.007
发表时间:
2015-07-13
期刊:
Cancer cell
影响因子:
50.3
作者:
[Flaveny CA, Griffett K, El-Gendy Bel-D, Kazantzis M, Sengupta M, Amelio AL, Chatterjee A, Walker J, Solt LA, Kamenecka TM, Burris TP]
通讯作者:
Burris TP
Biomarker Approach to Screening for the early detection of HPV-related Oropharyngeal Cancer (BASH OPC)
-
批准号:10769204
-
项目类别:
-
资助金额:$72.71万
-
财政年份:2023
-
负责人:Antonio Luigi Amelio
-
依托单位:
Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology
-
批准号:10615108
-
项目类别:
-
资助金额:$49.96万
-
财政年份:2022
-
负责人:Antonio Luigi Amelio
-
依托单位:
Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology
-
批准号:10747770
-
项目类别:
-
资助金额:$49.51万
-
财政年份:2022
-
负责人:Antonio Luigi Amelio
-
依托单位:
Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology
-
批准号:10296299
-
项目类别:
-
资助金额:$49.39万
-
财政年份:2021
-
负责人:Antonio Luigi Amelio
-
依托单位:
Illuminating the Role of Oral Stem Cells in the Development of Oral Squamous Cell Carcinomas
-
批准号:9346053
-
项目类别:
-
资助金额:$22.8万
-
财政年份:2016
-
负责人:Antonio Luigi Amelio
-
依托单位:
Convergence of CREB and MYC Pathways in Oncogenesis.
-
批准号:8930922
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2014
-
负责人:Antonio Luigi Amelio
-
依托单位:
Convergence of CREB and MYC Pathways in Oncogenesis.
-
批准号:8928274
-
项目类别:
-
资助金额:$24.15万
-
财政年份:2014
-
负责人:Antonio Luigi Amelio
-
依托单位:
Convergence of CREB and MYC Pathways in Oncogenesis.
-
批准号:8544427
-
项目类别:
-
资助金额:$14.72万
-
财政年份:2012
-
负责人:Antonio Luigi Amelio
-
依托单位:
Convergence of CREB and MYC Pathways in Oncogenesis.
-
批准号:8241509
-
项目类别:
-
资助金额:$14.72万
-
财政年份:2012
-
负责人:Antonio Luigi Amelio
-
依托单位:
Characterizing the Role of MYC-MAX Complexes in TORC1/MAML2-mediated Oncogenesis
-
批准号:7540099
-
项目类别:
-
资助金额:$4.96万
-
财政年份:2008
-
负责人:Antonio Luigi Amelio
-
依托单位:
Characterizing the Role of MYC-MAX Complexes in TORC1/MAML2-mediated Oncogenesis
-
批准号:7903865
-
项目类别:
-
资助金额:$5.17万
-
财政年份:2008
-
负责人:Antonio Luigi Amelio
-
依托单位:
Characterizing the Role of MYC-MAX Complexes in TORC1/MAML2-mediated Oncogenesis
-
批准号:7923184
-
项目类别:
-
资助金额:$5.38万
-
财政年份:2008
-
负责人:Antonio Luigi Amelio
-
依托单位:
海外基金