p53 and tumor cell metabolism
p53与肿瘤细胞代谢
基本信息
- 批准号:9307557
- 负责人:
- 金额:$ 33.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:AnabolismAntioxidantsBiomassCELSR1 geneCancer BiologyCellsCellular StressCitric Acid CycleDown-RegulationDrug Metabolic DetoxicationDrug TargetingEnzymesFeedbackGenesGlutamineHumanIsocitrate DehydrogenaseLinkMaintenanceMalignant NeoplasmsMediatingMetabolicMetabolic PathwayMetabolic stressMetabolismMutateMutationNADPNatureNutrientOutcomeOxidation-ReductionOxidative StressPathogenesisPathway interactionsPlayProductionProliferatingProtein IsoformsProtein p53ProteinsReactive Oxygen SpeciesRegulationResearchResearch ProposalsRoleSentinelTP53 geneTestingTherapeuticTissuesTumor Suppressioncancer therapycancer typefeedingglucose metabolismimprovedloss of functionmacromoleculemalic enzymeneoplastic cellnovel therapeuticsoxidative damageprotein protein interactionpublic health relevanceresponsesenescencetumortumor growthtumor metabolismtumorigenesisvirtual
项目摘要
DESCRIPTION (provided by applicant): This proposal aims to define the role of the tumor suppressor p53 in the regulation of metabolism, as well as the consequences of the loss of this function in tumor pathogenesis. p53 holds the distinction of being the most frequently mutated gene in human cancers, and its inactivation is essential not only for the formation of a remarkably wide range of tumors, but also for their continued survival and proliferation. Being able to understand the mechanism by which p53 suppresses tumorigenesis has been a central objective in cancer biology, one which has important implications in the treatment of a plethora of cancer types. Among the cellular response elicited by p53, emerging evidence has indicated that metabolic modulation and senescence are crucial for tumor suppression. Tumor cells rely on re-programmed metabolism to rapidly accumulate biomass and to effectively minimize oxidative damages. This proposal focuses on malic enzyme and isocitrate dehydrogenase (IDH). These are major enzymes that generate the reducing equivalent NADPH, which is essential for biosynthesis and anti-oxidant defense. They are also associated with the tricarboxylic acid cycle (TCA cycle), the central metabolic hub, and likely play critical roles in he metabolism of glucose and especially glutamine, two major nutrients for tumor cells. In our preliminary studies, we found previously unanticipated mutual regulation between p53 and malic enzymes. p53 suppresses the expression of malic enzymes, while down-regulation of malic enzymes reciprocally activates p53 and modulates the outcome of p53 activation, leading to senescence. Furthermore, we found that p53 suppresses the expression of IDH1, a major IDH isoform, in unstressed and especially stressed cells. These findings suggest that p53 may function as both a central sentinel and a master regulator of NADPH metabolism, linking the metabolic state of the cell with the cell fate decision. We plan to investigate the dynamic interplays between p53 and malic enzymes/IDH1. Our central hypothesis is that mutual regulation between malic enzymes and p53, as well as the suppression of IDH1 by p53, modulates biosynthesis and anti-oxidant response, and contributes to p53-mediated tumor suppression. We propose three specific aims: (1) Determine the functions of p53 and malic enzymes in glutamine metabolism; (2) Elucidate the role of p53 in regulating IDH1 and IDH1-assoicated metabolic fluxes; and (3) Define the role of malic enzymes in regulating p53 activation, anti-oxidant response, and senescence. The proposed studies will improve our understanding of key aspects of metabolic regulation and their link to p53-mediated cell fate decision, and may provide a rationale for targeting these NADPH-generating enzymes as a new therapy for cancer.
描述(由申请人提供):本提案旨在确定肿瘤抑制因子p53在代谢调节中的作用,以及在肿瘤发病机制中丧失该功能的后果。p53具有作为人类癌症中最频繁突变的基因的特征,并且其失活不仅对于非常广泛的肿瘤的形成是必需的,而且对于它们的持续存活和增殖也是必需的。能够理解p53抑制肿瘤发生的机制一直是癌症生物学的中心目标,这对治疗多种癌症类型具有重要意义。在p53引起的细胞反应中,新出现的证据表明代谢调节和衰老对于肿瘤抑制至关重要。肿瘤细胞依赖于重新编程的代谢来快速积累生物量并有效地最小化氧化损伤。该建议的重点是苹果酸酶和异柠檬酸脱氢酶(IDH)。这些是产生还原当量NADPH的主要酶,还原当量NADPH对于生物合成和抗氧化防御是必需的。它们还与三羧酸循环(TCA循环)(中心代谢中心)相关,并可能在葡萄糖尤其是谷氨酰胺(肿瘤细胞的两种主要营养物质)的代谢中发挥关键作用。在我们的初步研究中,我们发现了以前没有预料到的p53和苹果酸酶之间的相互调节。p53抑制苹果酸酶的表达,而苹果酸酶的下调可激活p53并调节p53激活的结果,导致衰老。此外,我们发现p53抑制未应激和尤其是应激细胞中IDH 1(一种主要IDH亚型)的表达。这些发现表明,p53可能作为一个中央哨兵和NADPH代谢的主调节器,连接细胞的代谢状态与细胞命运的决定。我们计划研究p53和苹果酸酶/IDH 1之间的动态相互作用。我们的中心假设是苹果酸酶和p53之间的相互调节,以及p53对IDH 1的抑制,调节生物合成和抗氧化反应,并有助于p53介导的肿瘤抑制。我们提出了三个具体目标:(1)确定p53和苹果酸酶在谷氨酰胺代谢中的功能;(2)阐明p53在调节IDH 1和IDH 1相关代谢通量中的作用;(3)确定苹果酸酶在调节p53激活,抗氧化反应和衰老中的作用。拟议的研究将提高我们对代谢调节的关键方面及其与p53介导的细胞命运决定的联系的理解,并可能为靶向这些NADPH生成酶作为癌症的新疗法提供理论基础。
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 }}
Xiaolu Yang其他文献
Xiaolu Yang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('Xiaolu Yang', 18)}}的其他基金
Regulation of the ERK signaling pathway by K63-linked polyubiquitination
K63 连接的多聚泛素化对 ERK 信号通路的调节
- 批准号:
10701811 - 财政年份:2022
- 资助金额:
$ 33.2万 - 项目类别:
Regulation of the ERK signaling pathway by K63-linked polyubiquitination
K63 连接的多聚泛素化对 ERK 信号通路的调节
- 批准号:
10535249 - 财政年份:2022
- 资助金额:
$ 33.2万 - 项目类别:
A novel protein quality control system and its role in tumorigenesis
一种新型蛋白质质量控制系统及其在肿瘤发生中的作用
- 批准号:
9917186 - 财政年份:2020
- 资助金额:
$ 33.2万 - 项目类别:
A novel protein quality control system and its role in tumorigenesis
一种新型蛋白质质量控制系统及其在肿瘤发生中的作用
- 批准号:
10399408 - 财政年份:2020
- 资助金额:
$ 33.2万 - 项目类别:
A novel protein quality control system and its role in tumorigenesis
一种新型蛋白质质量控制系统及其在肿瘤发生中的作用
- 批准号:
10558619 - 财政年份:2020
- 资助金额:
$ 33.2万 - 项目类别:
Role of Daxx in protein folding and tumorigenesis
Daxx 在蛋白质折叠和肿瘤发生中的作用
- 批准号:
10689110 - 财政年份:2019
- 资助金额:
$ 33.2万 - 项目类别:
Role of Daxx in protein folding and tumorigenesis
Daxx 在蛋白质折叠和肿瘤发生中的作用
- 批准号:
10495196 - 财政年份:2019
- 资助金额:
$ 33.2万 - 项目类别:
Role of the pentose phosphate pathway in tumorigenesis
磷酸戊糖途径在肿瘤发生中的作用
- 批准号:
9236169 - 财政年份:2016
- 资助金额:
$ 33.2万 - 项目类别:
Role of the pentose phosphate pathway in tumorigenesis
磷酸戊糖途径在肿瘤发生中的作用
- 批准号:
9101315 - 财政年份:2016
- 资助金额:
$ 33.2万 - 项目类别:
Role of p53 family proteins in glucose metabolism
p53家族蛋白在葡萄糖代谢中的作用
- 批准号:
8846081 - 财政年份:2014
- 资助金额:
$ 33.2万 - 项目类别:
相似海外基金
Enhancing gamete cryoprotective properties of graphene oxide by dual functionalization with antioxidants and non-penetrating cryoprotectant molecules
通过抗氧化剂和非渗透性冷冻保护剂分子的双重功能化增强氧化石墨烯的配子冷冻保护特性
- 批准号:
24K18002 - 财政年份:2024
- 资助金额:
$ 33.2万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
SBIR Phase I: Sustainable antioxidants for industrial process fluids
SBIR 第一阶段:工业过程流体的可持续抗氧化剂
- 批准号:
2222215 - 财政年份:2023
- 资助金额:
$ 33.2万 - 项目类别:
Standard Grant
Development of a new bone augmentation method that enables long-term survival and long-term functional expression of transplanted cells by antioxidants
开发一种新的骨增强方法,通过抗氧化剂使移植细胞能够长期存活和长期功能表达
- 批准号:
23K09272 - 财政年份:2023
- 资助金额:
$ 33.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Non-Invasive Probing Cellular Oxidative Stress and Antioxidants Therapeutic Effectiveness
非侵入性探测细胞氧化应激和抗氧化剂的治疗效果
- 批准号:
10652764 - 财政年份:2023
- 资助金额:
$ 33.2万 - 项目类别:
Mitochondria-targeting Novel Cationic Hydrazone Antioxidants for the Treatment of Preeclampsia
线粒体靶向新型阳离子腙抗氧化剂用于治疗先兆子痫
- 批准号:
10730652 - 财政年份:2023
- 资助金额:
$ 33.2万 - 项目类别:
Effects of different doses of antioxidants(Vitamin E) intake on exercise induced oxidative stress, antioxidative capacity and chronic inflammation
不同剂量抗氧化剂(维生素E)摄入对运动引起的氧化应激、抗氧化能力和慢性炎症的影响
- 批准号:
22K11609 - 财政年份:2022
- 资助金额:
$ 33.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Contribution of antioxidants to regeneration of rotator cuff insertion
抗氧化剂对肩袖插入再生的贡献
- 批准号:
22K16720 - 财政年份:2022
- 资助金额:
$ 33.2万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Latent Antioxidants for Environmentally Responsible Polymer Formulations
用于环保聚合物配方的潜在抗氧化剂
- 批准号:
RGPIN-2018-04107 - 财政年份:2022
- 资助金额:
$ 33.2万 - 项目类别:
Discovery Grants Program - Individual
Polyunsaturated fatty acid (PUFA), inflammation and antioxidants
多不饱和脂肪酸 (PUFA)、炎症和抗氧化剂
- 批准号:
RGPIN-2019-05674 - 财政年份:2022
- 资助金额:
$ 33.2万 - 项目类别:
Discovery Grants Program - Individual
Suppressed methemoglobin formation of artificial red cell by liposomal antioxidants and its mechanism.
脂质体抗氧化剂抑制人工红细胞高铁血红蛋白形成及其机制
- 批准号:
22K12824 - 财政年份:2022
- 资助金额:
$ 33.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)