Biological Roles of the Prolyl Isomerase, PIN1
脯氨酰异构酶 PIN1 的生物学作用
基本信息
- 批准号:7415031
- 负责人:
- 金额:$ 31.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-08-06 至 2010-04-30
- 项目状态:已结题
- 来源:
- 关键词:19p1319p13.3AddressAllelesAmidesAnimalsAspergillus nidulansAttentionBindingBinding ProteinsBinding SitesBiochemistryBiologicalBiological AssayC-terminalCell CycleCell Cycle ProgressionCell Cycle RegulationCellsCellular biologyChromosomesComplexConsensusCyclin ECyclin-Dependent KinasesDevelopmentDominant-Negative MutationE proteinEmbryonic DevelopmentEnzymesEvaluationEventFamilyFibroblastsFungal ProteinsG2/M TransitionGenesGeneticGenetic RecombinationGenetically Engineered MouseGenomic InstabilityGrowthHumanHybridsKnockout MiceLoss of HeterozygosityMAP Kinase GeneMalignant NeoplasmsMediatingMitogensMitosisMusN-terminalNIMANatureNull LymphocytesObject AttachmentOncogenicPeptidylprolyl IsomerasePhenotypePhosphorylationPhosphotransferasesPin1 proteinPlayPredispositionProcessProlineProtein DephosphorylationProtein IsoformsProtein KinaseProtein Phosphatase 2A Regulatory Subunit PR53ProteinsRateReportingResearchResearch PersonnelRoleSCF(Fbw7) Ubiquitin LigaseSeriesSerineSignal TransductionSpecificitySpecimenStructure of primordial sex cellSubstrate SpecificitySystemTP53 geneTestingThreonineTimeTumor PromotersTumor Suppressor ProteinsXenopusYeastsc-myc Genescarcinogenesiscell immortalizationcell transformationcell typedayfascinatefungusgenetic regulatory proteinhuman CCNE1 proteininterestkillingsloss of functionmouse modelnovelprogramstumortumorigenesis
项目摘要
DESCRIPTION (provided by applicant): The overarching hypothesis of the proposed research is that loss of function of the Pin1 prolyl isomerase can result in differential susceptibility to tumorigenesis. Pin1 was originally identified as a regulator of a fungal protein kinase required for mitosis and so was suggested to play important roles in cell cycle progression. It is now known that Pin1 functions in both G1 and G2 of the cell cycle and several Pin1 binding proteins that also play important roles in the cell cycle have been identified. Pin1 binds to proteins phosphorylated on pSer/pThr-Pro motifs and isomerization of the prolyl amide bond can cause a conformational change that regulates the abundance of the target protein in the cell either in a positive or negative manner. Pin1 has been implicated to be important in human cancers not only because it is involved in cell cycle regulation but also as several studies have reported either increased levels of Pin1 in human tumor specimens or Loss of Heterozygosity of the portion of chromosome 19p13.3 that contains Pin1. Thus, the question of whether the loss of Pin1 could, depending on the genetic background, either sensitize or protect cells from transformation remains enigmatic. Evaluation of fibroblasts from Pin1 null mice in a pure C57BL6/J genetic background revealed two novel target proteins for Pin1 to be c-Myc, and cyclin E1. Pin1 regulates the degradation of c- Myc. The absence of Pin1 from immortalized mouse fibroblasts increases c-Myc and cyclin E1 levels, results in genomic instability and renders these cells sensitive to Ras-mediated transformation. To extend these remarkably provocative results and address this fascinating conundrum, it is proposed to: 1) evaluate the mechanism of action of Pin1 by using NMR to determine how Pin1 binds to c-Myc and biochemistry/cell biology to evaluate whether Pin1 regulates accumulation of cyclin E1 as it does c-Myc; 2) examine how the loss of function of Pin1 contributes to genomic instability in immortalized mouse fibroblasts; and 3) test the hypothesis that loss of function of Pint can alter the timing of tumorigenesis in a genetically engineered mouse model of cancer wherein spontaneous recombination in whole animals is necessary to activate an oncogenic allele of K-Ras, which in turn leads to tumorigenesis in 100% of the mice by 300 days. We hope that completion of these proposed studies will help to clarify the potential role of Pin1 and/or its target proteins in carcinogenesis.
描述(由申请人提供):拟议研究的主要假设是Pin1 Pro异构酶功能的丧失可导致肿瘤发生的不同易感性。Pin1最初被认为是有丝分裂所需的真菌蛋白激酶的调节因子,因此被认为在细胞周期进程中发挥重要作用。目前已知Pin1在细胞周期的G1和G2中都有功能,并且已经确定了几种在细胞周期中发挥重要作用的Pin1结合蛋白。Pin1与pSer/pThr-Pro基序上磷酸化的蛋白质结合,Pro-酰胺键的异构化可以引起构象变化,以积极或消极的方式调节目标蛋白在细胞中的丰度。Pin1被认为在人类癌症中很重要,这不仅是因为它参与了细胞周期调节,而且因为一些研究报告了人类肿瘤标本中Pin1水平的增加或含有Pin1的染色体19p13.3部分的杂合性丢失。因此,根据遗传背景,Pin1的缺失是否会使细胞变得敏感或保护细胞免受转化的影响,这个问题仍然是个谜。在纯C57BL6/J遗传背景中对Pin1基因缺失小鼠成纤维细胞的评估发现,Pin1的两个新的靶蛋白是c-Myc和Cyclin E1。Pin1调控c-Myc的降解。永生化的小鼠成纤维细胞中缺乏Pin1基因会增加c-Myc和细胞周期蛋白E1的水平,导致基因组不稳定,并使这些细胞对RAS介导的转化敏感。为了推广这些显著具有挑衅性的结果并解决这一令人着迷的难题,有人建议:1)通过核磁共振确定Pin1如何与c-Myc结合来评估Pin1的作用机制,并通过生物化学/细胞生物学来评估Pin1是否像它对c-Myc一样调节细胞周期蛋白E1的积累;2)研究Pin1功能的丧失如何导致永生化小鼠成纤维细胞基因组的不稳定;以及3)在基因工程小鼠癌症模型中测试Pint功能丧失可以改变肿瘤发生时间的假设,在该模型中,整个动物的自发重组是激活K-RAS的致癌等位基因所必需的,这反过来又导致在300天内100%的小鼠发生肿瘤。我们希望这些拟议研究的完成将有助于阐明Pin1和/或其靶蛋白在癌症发生中的潜在作用。
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 }}
ANTHONY R MEANS其他文献
ANTHONY R MEANS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('ANTHONY R MEANS', 18)}}的其他基金
Hormonal regulation of a Ca2+/AMPK signaling pathway
Ca2 /AMPK 信号通路的激素调节
- 批准号:
8059067 - 财政年份:2010
- 资助金额:
$ 31.03万 - 项目类别:
BIOLOGICAL ROLES OF THE PROLYL ISOMERASE, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
2898838 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
BIOLOGICAL ROLES OF THE PROLYL ISOMERASE, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
6514156 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
Biological Roles of the Prolyl Isomerase, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
7610946 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
BIOLOGICAL ROLES OF THE PROLYL ISOMERASE, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
6174122 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
Biological Roles of the Prolyl Isomerase, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
6985074 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
Biological Roles of the Prolyl Isomerase, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
7067629 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
BIOLOGICAL ROLES OF THE PROLYL ISOMERASE, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
6633499 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
BIOLOGICAL ROLES OF THE PROLYL ISOMERASE, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
6377435 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
相似海外基金
Biological Roles of the Prolyl Isomerase, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
7610946 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
Biological Roles of the Prolyl Isomerase, PIN1
脯氨酰异构酶 PIN1 的生物学作用
- 批准号:
7232416 - 财政年份:1999
- 资助金额:
$ 31.03万 - 项目类别:
Altered LKB1/AMPK Signaling and Chemosensitivity in NSCLC
NSCLC 中 LKB1/AMPK 信号传导和化疗敏感性的改变
- 批准号:
7481156 - 财政年份:
- 资助金额:
$ 31.03万 - 项目类别:
Altered LKB1/AMPK Signaling and Chemosensitivity in NSCLC
NSCLC 中 LKB1/AMPK 信号传导和化疗敏感性的改变
- 批准号:
7849563 - 财政年份:
- 资助金额:
$ 31.03万 - 项目类别:
Altered LKB1/AMPK Signaling and Chemosensitivity in NSCLC
NSCLC 中 LKB1/AMPK 信号传导和化疗敏感性的改变
- 批准号:
8119040 - 财政年份:
- 资助金额:
$ 31.03万 - 项目类别: