Molecular basis of gene-specific function of p53K120 acetylation in proapoptotic gene transcription - Resubmission - 1
p53K120 乙酰化在促凋亡基因转录中的基因特异性功能的分子基础 - Resubmission - 1
基本信息
- 批准号:10212965
- 负责人:
- 金额:$ 7.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylationApoptosisApoptoticAreaBAX geneBindingBiochemicalBiological AssayCDKN1A geneCell Cycle ArrestCell physiologyCellsChromatinCommunicationComplexDNA BindingDNA DamageDNA RepairDevelopmentEnhancersFrequenciesGene ActivationGenesGeneticGenetic TranscriptionGenomeHCT116 CellsHTATIP geneHistonesHomeostasisHumanIn VitroKineticsLaboratoriesLightLysineMDM2 geneMalignant NeoplasmsMediatingMediator of activation proteinMetabolic stressMetabolismMethylationMissense MutationMolecularMutateMutationOncogenicOutcomePMAIP1 genePTEN genePeptide Initiation FactorsPhosphorylationPhysiologicalPost-Translational Protein ProcessingProteinsProteomicsProthrombinRNA Polymerase IIReportingResearchRoleSiteStressSystemTP53 geneTestingTranscription CoactivatorTranscription InitiationTranscriptional ActivationTransferaseTumor BiologyTumor SuppressionTumor Suppressor Proteinsbasebiological adaptation to stresscancer therapychromatin remodelingcofactorgenotoxicityin vivoinsightinterestknock-downmutantnovelpromoterprotein protein interactionrecruitresponse
项目摘要
“Molecular basis of gene-specific function of p53K120 acetylation in proapoptotic gene transcription”
PROJECT SUMMARY
p53 is a tumor suppressor whose gene is the most commonly mutated gene in human cancer. As the “guardian
of the genome”, p53 is stabilized and activated by various genotoxic, oncogenic and metabolic stresses (amongst
others). As a conventional site-specific DNA-binding transcriptional activator, p53 activates a broad array of
target genes that in turn regulate many cellular processes that include cell cycle arrest, DNA repair, apoptosis,
auto-regulation, and metabolism. Like other transcriptional activators, enhancer/promoter-bound p53 interacts
with diverse co-activators that include chromatin remodeling/histone modifying factors and other factors (e.g.,
Mediator and TAFs) that mediate direct communication with RNA polymerase II and the general transcription
initiation factors (GTFs) at core promoters. In response to stress, the function of p53 is subject to numerous post-
translational modifications that include phosphorylation, acetylation and methylation. Two major outcomes of
DNA damage-mediated activation of p53 are cell-cycle arrest and apoptosis. The basis for the choice between
cell-cycle arrest and apoptosis in a stress response is poorly understood, but dependent in part on the extent of
the stress and the cellular context. Several studies have reported cofactors that are selectively involved in p53-
dependent transcription of proapoptotic genes, although the mechanisms underlying their gene-selective
functions are not clear. Two groups have shown that DNA damage-induced p53 K120 acetylation is critical for
transcription of key proapoptotic genes (PUMA and BAX) but not proarrest (p21) or p53 autoregulatory (HDM2)
genes. The further observation that p53 binding to PUMA and BAX is independent of K120 acetylation leads to
the hypothesis that p53K120ac acts through interactions with a specific cofactor(s), potentially one of the
previously identified proapoptotic factors or an as yet unidentified factor. The proposed project will seek to identify
and elucidate the mechanism of action of cofactors that directly mediate the pro-apoptotic gene-specific functions
of p53K120ac. In Aim 1, biochemical and cell-based approaches with DNA-damaged HCT116 cells will be
employed to identify and validate (i) proapoptotic gene-associated factors dependent upon p53 K120 acetylation
(by ChIP analysis) and (ii) p53K120ac-interacting/associated proteins (by proteomic analyses). In Aim 2,
integrated cell-based (gene editing/protein knockdown) and biochemical approaches will be used to establish (i)
intracellular proapoptotic gene-specific functions of p53K120ac cofactors, (ii) kinetics of cofactor association with
PUMA and BAX versus p21 and MDM2 genes, (iii) p53K120ac cofactor-dependent, gene-specific transcription
of PUMA in vitro; and (iv) the mechanism of action of p53K120ac and associated cofactors through various
protein-protein interactions. These studies will shed new light on a key proapoptotic function of p53 in tumor
suppression.
“p53 K120乙酰化在促凋亡基因转录中基因特异性功能的分子基础”
项目摘要
p53是一种肿瘤抑制基因,其基因是人类癌症中最常见的突变基因。作为“守护者
p53被各种遗传毒性、致癌性和代谢应激(其中
其他)。作为一种常规的位点特异性DNA结合转录激活因子,p53激活了一系列广泛的转录因子。
靶基因反过来调节许多细胞过程,包括细胞周期停滞、DNA修复、凋亡
自动调节和新陈代谢。与其他转录激活因子一样,增强子/启动子结合的p53相互作用
与包括染色质重塑/组蛋白修饰因子和其它因子(例如,
介导因子和TAF),介导与RNA聚合酶II和一般转录的直接通讯
起始因子(GTF)。在应激反应中,p53的功能受到许多后-
翻译修饰包括磷酸化、乙酰化和甲基化。两大成果
DNA损伤介导的p53激活是细胞周期阻滞和凋亡。选择的基础是
应激反应中的细胞周期停滞和凋亡知之甚少,但部分取决于应激反应的程度。
压力和细胞环境。一些研究报道了选择性参与p53的辅因子,
依赖于促凋亡基因的转录,尽管其基因选择性
功能不明确。两个研究小组已经表明,DNA损伤诱导的p53 K120乙酰化对于
关键的促凋亡基因(p21和BAX)的转录,但不是促凋亡基因(p21)或p53自身调节基因(HDM 2)的转录
基因.进一步观察到p53与K120和BAX的结合不依赖于K120乙酰化,
p53 K120 ac通过与特定辅因子相互作用而起作用的假设,可能是
先前鉴定的促凋亡因子或尚未鉴定的因子。拟议项目将寻求确定
并阐明直接介导促凋亡基因特异性功能的辅因子的作用机制
p53k120ac在目标1中,将使用DNA损伤的HCT 116细胞的生物化学和基于细胞的方法,
用于鉴定和验证(i)依赖于p53 K120乙酰化的促凋亡基因相关因子
(by ChIP分析)和(ii)p53 K120 ac相互作用/相关蛋白(通过蛋白质组学分析)。在目标2中,
整合的基于细胞的(基因编辑/蛋白质敲减)和生物化学方法将用于建立(i)
p53 K120 ac辅因子细胞内促凋亡基因特异性功能,(ii)辅因子与
p53 K120 ac辅因子依赖性基因特异性转录
p53 K120 ac和相关辅因子通过各种途径的作用机制
蛋白质相互作用这些研究将为p53在肿瘤中的关键促凋亡功能提供新的线索
镇压
项目成果
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