Structural basis for CBP/p300 transcriptional regulation
CBP/p300 转录调控的结构基础
基本信息
- 批准号:7909484
- 负责人:
- 金额:$ 5.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2010-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAddressAdenovirus E1A ProteinsAffectAffinityApoptosisBindingBinding SitesBiological AssayCREB-binding proteinCell Cycle RegulationCell physiologyCellular StressCollaborationsComplexDNA RepairDataDifferentiation and GrowthEP300 geneEmbryonic DevelopmentEukaryotic CellEventGenetic TranscriptionGenotoxic StressGoalsGrowthIndividualInfectionLibrariesMDM2 geneMeasuresMediatingModelingMolecularMultiple PartnersN-terminalNormal CellNuclearOncogene ProteinsOncogenicOncogenic VirusesPhosphorylationPlayProliferatingPropertyProtein p53ProteinsResearchRetinoblastoma ProteinRoentgen RaysRoleSerotypingSignal Transduction PathwaySiteStructureTP53 geneTertiary Protein StructureTransactivationTranscription CoactivatorTranscriptional RegulationTumor SuppressionTumor Suppressor ProteinsViralViral Oncogenebasecell immortalizationhuman CREBBP proteinimmortalized cellin vitro testingin vivoinsightmolecular recognitionnon-oncogenicrepairedresearch studyresponseretinoblastoma tumor suppressortranscription factor
项目摘要
DESCRIPTION (provided by applicant): CREB binding protein (CBP) and p300 are modular transcriptional coactivators that integrate numerous signal transduction pathways in eukaryotic cells, and are essential for growth, differentiation, apoptosis, and DNA repair. CBP/p300 play critical roles in embryonic development and are the targets of many oncogenic events. They also function as tumor suppressors and are required for the transcriptional activities of many cellular and tumor virus oncoproteins. CBP and p300 play an essential role in mediating the stability and transcriptional activity of the tumor suppressor p53. The interactions between these proteins are highly dynamic and are modulated by phosphorylation of the p53 transactivation domain at multiple sites in response to genotoxic stress. The adenoviral oncoprotein E1A competes with cellular factors to sequester CBP/p300, disrupting normal cell cycle control to induce cell immortalization. This research will utilize an extensive library of protein constructs to investigate the interactions of p53 and E1A with the TAZ1, TAZ2, KIX, and nuclear coactivator binding domains of CBP. The structures of the complexes formed by the bipartite N-terminal transactivation domain of p53 with the CBP domains will be determined, to obtain new insights into the dynamic interplay of interactions between the domains and into the molecular basis for CBP/p300 activation of p53-regulated transcription. The effects of phosphorylation of the p53 transactivation domain, at single and multiple sites, on interactions with these domains will be investigated. Structures will be determined for the complexes formed by E1A (both non-oncogenic AdV5 and strongly oncogenic AdV12 serotypes), with domains of CBP/p300, in order to obtain insights into the molecular basis by which E1A competes with other transcription factors to sequester CBP/p300 and subvert the cellular transcription machinery. Finally, two ternary complexes will be characterized, between HDM2, p53, and the TAZ1 domain of CBP, and between the pocket domain of the retinoblastoma protein Rb, E1A and the TAZ2 domain. With its emphasis on weak, competing interactions and the synergistic interplay between multiple binding sites and multiple partners, this research will provide new and fundamental insights into the mechanisms of molecular recognition by CBP/p300, and the molecular basis by which they mediate critical interactions with p53 and viral oncoproteins in tumor suppression, growth and progression.
描述(由申请人提供):CREB结合蛋白(CBP)和p300是模块化转录共激活因子,整合真核细胞中的多种信号转导途径,对生长、分化、凋亡和DNA修复至关重要。CBP/p300在胚胎发育中起关键作用,是许多致癌事件的靶点。它们还具有肿瘤抑制的功能,是许多细胞和肿瘤病毒癌蛋白转录活动所必需的。CBP和p300在调节肿瘤抑制因子p53的稳定性和转录活性中发挥重要作用。这些蛋白之间的相互作用是高度动态的,并在基因毒性应激反应中通过p53反活化结构域在多个位点的磷酸化来调节。腺病毒癌蛋白E1A与细胞因子竞争,隔离CBP/p300,破坏正常的细胞周期控制,诱导细胞永生。本研究将利用广泛的蛋白质构建文库来研究p53和E1A与CBP的TAZ1、TAZ2、KIX和核辅激活子结合域的相互作用。将确定p53的二部n端反激活结构域与CBP结构域形成的复合物的结构,以获得结构域之间相互作用的动态相互作用以及CBP/p300激活p53调控转录的分子基础的新见解。p53反活化结构域的单位点和多位点磷酸化对这些结构域相互作用的影响将被研究。将确定E1A(非致癌性AdV5和强致癌性AdV12血清型)与CBP/p300结构域形成的复合物的结构,以便深入了解E1A与其他转录因子竞争以隔离CBP/p300并破坏细胞转录机制的分子基础。最后,两个三元复合物将被表征,在HDM2、p53和CBP的TAZ1结构域之间,以及在视网膜母细胞瘤蛋白Rb、E1A的口袋结构域和TAZ2结构域之间。该研究强调弱的、竞争的相互作用以及多个结合位点和多个伙伴之间的协同相互作用,将为CBP/p300的分子识别机制,以及它们介导p53和病毒癌蛋白在肿瘤抑制、生长和进展中的关键相互作用的分子基础提供新的和基础的见解。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PETER Edwin WRIGHT其他文献
PETER Edwin WRIGHT的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('PETER Edwin WRIGHT', 18)}}的其他基金
Structural characterization of large eukaryotic proteins containing both folded and disordered domains
含有折叠和无序结构域的大型真核蛋白质的结构表征
- 批准号:
10552345 - 财政年份:2023
- 资助金额:
$ 5.55万 - 项目类别:
Molecular mechanisms of transthyretin amyloidosis
运甲状腺素蛋白淀粉样变性的分子机制
- 批准号:
10115719 - 财政年份:2020
- 资助金额:
$ 5.55万 - 项目类别:
Molecular mechanisms of transthyretin amyloidosis
运甲状腺素蛋白淀粉样变性的分子机制
- 批准号:
10599188 - 财政年份:2020
- 资助金额:
$ 5.55万 - 项目类别:
Molecular mechanisms of transthyretin amyloidosis
运甲状腺素蛋白淀粉样变性的分子机制
- 批准号:
10372930 - 财政年份:2020
- 资助金额:
$ 5.55万 - 项目类别:
Molecular Basis for Regulation of Cellular Stress Response Pathways by CBP/p300
CBP/p300 调节细胞应激反应途径的分子基础
- 批准号:
10436187 - 财政年份:2018
- 资助金额:
$ 5.55万 - 项目类别:
Molecular Basis for Regulation of Cellular Stress Response Pathways by CBP/p300
CBP/p300 调节细胞应激反应途径的分子基础
- 批准号:
10172869 - 财政年份:2018
- 资助金额:
$ 5.55万 - 项目类别:
High Performance Digital NMR Spectrometer Console
高性能数字核磁共振波谱仪控制台
- 批准号:
7793710 - 财政年份:2010
- 资助金额:
$ 5.55万 - 项目类别:
Recognition of Regulatory and Pathogenic RNA by Muscleblind Zinc Fingers
肌盲锌指识别调节性和致病性 RNA
- 批准号:
7924930 - 财政年份:2009
- 资助金额:
$ 5.55万 - 项目类别:
International Conference on Magnetic Resonance in Biological Systems 2008
2008 年生物系统磁共振国际会议
- 批准号:
7483664 - 财政年份:2008
- 资助金额:
$ 5.55万 - 项目类别:
NMR STRUCTURAL STUDIES OF PRION PROTEINS WITH POINT MUTATIONS
点突变朊病毒蛋白的核磁共振结构研究
- 批准号:
7447340 - 财政年份:2007
- 资助金额:
$ 5.55万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 5.55万 - 项目类别:
Research Grant