F-box ubiquitin ligases destabilize neurofibromin
F-box ubiquitin ligases destabilize neurofibromin
批准号:
9767890
负责人:
David W Clapp
金额:
$34.45万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-01 至 2023-08-31
关键词:
AffectAllelesAutomobile DrivingB-LymphocytesBiochemicalBone MarrowBone Marrow TransplantationCellsChemotaxisClinicalComplexF Box DomainF-Box ProteinsFamilyGTPase-Activating ProteinsGenesGeneticGenetically Engineered MouseGenomeGenomic approachGlioblastomaGrowth FactorHematopoieticHematopoietic SystemHematopoietic stem cellsHeterogeneityHumanHuman GeneticsIndividualInflammatoryKnockout MiceLesionMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMediatingMetastatic MelanomaMorbidity - disease rateMusMutationMyeloid CellsNF1 geneNeurofibromatosesNeurofibromatosis 1Neurofibromatosis Type 1 ProteinNon-MalignantPathologicPathway interactionsPatientsPharmacological TreatmentPhase II Clinical TrialsPhenotypePhosphorylationPhosphotransferasesPlexiform NeurofibromaPre-Clinical ModelPredispositionPremalignantPreparationProcessProteinsRNA interference screenRadiation therapyRegulationResistanceSignal PathwaySignal TransductionSmall Interfering RNASpecificityStem Cell FactorSyndromeTestingTissuesTumor Suppressor GenesTumor Suppressor ProteinsUbiquitinUbiquitinationWorkcancer geneticschemotherapyclinically significantdrug discoveryfunctional genomicsin vivoinnovationinsightinterdisciplinary approachkinase inhibitormast cellmortalitymulticatalytic endopeptidase complexnovelpatient responsepreventrecruitresponsescreeningsuccesstherapeutic candidatetherapeutic targettumortumorigenesisubiquitin ligaseubiquitin-protein ligase
中文摘要
项目总结/摘要
NF 1肿瘤抑制基因的突变导致1型神经纤维瘤病(NF 1),这是人类最常见的
遗传性癌症易感综合征患有NF 1的个体患有广泛的恶性肿瘤,
非恶性临床表现包括丛状神经纤维瘤(PN),复杂的癌前病变
其影响25-40%的NF 1患者并导致主要的终身发病率和死亡率。NF 1基因编码
neurofibromin,一种p21 ras(Ras)的GTP酶激活蛋白(GAP)。我们先前确定,
Nf 1单个等位基因(Nf 1 +/-)导致Nf 1患者(Nf 1 +/-)和鼠(Nf 1 +/-)骨髓细胞中Ras过度活化,
这个概念被称为单倍不足。我们建立了一个基因工程小鼠模型,
神经纤维瘤病,并证明丛状神经纤维瘤的形成需要炎性
Nf 1 +/-骨髓的贡献。此外,我们发现,下游激酶通路的遗传抑制
造血系统中的神经纤维蛋白酶可防止肿瘤发生。这项工作导致了有史以来第一次
在临床前模型和我们的II期临床试验中,这些肿瘤的成功药物治疗。
尽管取得了这一成功,但在神经纤维蛋白酶缺乏的组织中纠正Ras过度活化的补充策略
由于Ras介导的信号通路的复杂性和患者反应的异质性,
对于这些复杂肿瘤的激酶抑制剂,这些肿瘤对传统化疗完全抵抗,
放射治疗
神经纤维蛋白被磷酸化,泛素化,并在蛋白酶体降解,以响应生长因子
刺激,但很少有人知道这个过程的机制方面。具体来说,泛素连接酶
控制肿瘤驱动造血细胞中神经纤维蛋白降解的特异性因子(E3)不
知道的F-box泛素连接酶以磷酸化依赖的方式降解选定的蛋白质,导致蛋白质的磷酸化。
我们假设NF 1 E3属于F-box家族。在最初未发表的研究中,
为了准备这个应用,我们进行了RNAi筛选,鉴定了强的新候选F-box
NF 1的泛素连接酶。在这里,我们建议机械地检查这些新发现的F盒蛋白质
调节离体和体内神经纤维蛋白降解。我们还建议采用一个无偏泛函
基因组学策略,以鉴定促进神经纤维蛋白的F-box依赖性降解的激酶,
泛素-蛋白酶体途径我们将采用多学科的方法来确定是否中断
我们的候选神经纤维蛋白E3在体内可以挽救神经纤维蛋白单倍不足,
神经纤维瘤的发生和发展。这些研究还将提供基本的见解,
常见但研究不足的肿瘤抑制基因。
英文摘要
PROJECT SUMMARY / ABSTRACT
Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), the most common human
genetic cancer predisposition syndrome. Individuals with NF1 suffer from a wide range of malignant and
nonmalignant clinical manifestations including plexiform neurofibromas (PN), complex precancerous lesions
which affect 25-40% of NF1 patients and cause major lifelong morbidity and mortality. The NF1 gene encodes
neurofibromin, a GTPase-activating protein (GAP) for p21ras (Ras). We previously determined that loss of a
single allele of Nf1 (Nf1+/-) results in Ras hyperactivation in NF1 patient (NF1+/-) and murine (Nf1+/-) myeloid cells,
a concept known as haploinsufficiency. We generated a genetically engineered murine model of
neurofibromatosis and demonstrated that plexiform neurofibroma formation requires the inflammatory
contribution of Nf1+/- bone marrow. Further, we showed that genetic inhibition of kinase pathways downstream
of neurofibromin in the hematopoietic system prevents tumorigenesis. This work has led to the first ever
successful pharmacological treatment of these tumors in both preclinical models and in our phase II clinical trial.
Despite this success, complementary strategies to correct Ras hyperactivation in neurofibromin-deficient tissues
are needed due to the complexity of Ras-mediated signaling pathways and the heterogeneity of patient response
to kinase inhibitors for these complex tumors that are completely resistant to traditional chemotherapy and
radiation treatment.
Neurofibromin is phosphorylated, ubiquitinated, and degraded at the proteasome in response to growth factor
stimulation, but little is known about the mechanistic aspects of this process. Specifically, the ubiquitin ligase
specificity factor(s) (E3) that govern neurofibromin degradation in the tumor-driving hematopoietic cells are not
known. The F-box ubiquitin ligases degrade selected proteins in a phosphorylation-dependent manner, leading
us to hypothesize that the NF1 E3 belongs to the F-box family. In initial unpublished studies pursued in
preparation for this application, we conducted an RNAi screen, which identified strong novel candidate F-box
ubiquitin ligases for NF1. Here, we propose to mechanistically examine these newly identified F-box proteins
modulating neurofibromin degradation ex vivo and in vivo. We also propose to employ an unbiased functional
genomics strategy to identify kinase(s) that promote F-box-dependent degradation of neurofibromin via the
ubiquitin-proteasome pathway. We will employ a multidisciplinary approach to determine whether disruption of
our candidate neurofibromin E3s in vivo can rescue neurofibromin haploinsufficiency and prevent plexiform
neurofibroma initiation and progression. These studies will also provide basic insights into the regulation of a
common but understudied tumor suppressor gene.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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Preclinical-clinical trials collaboration to effectively advance new combination therapies for atypical neurofibroma in neurofibromatosis type 1
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The Medical Physician Engineers, Scientists, and Clinicians Preparatory Program [MPESC-Prep]
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TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors
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Mitotic failure in Fanconi anemia: mechanisms and role in carcinogenesis
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依托单位:
F-box ubiquitin ligases destabilize neurofibromin
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资助金额:$34.45万
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依托单位:
F-box ubiquitin ligases destabilize neurofibromin
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Developmental and Hyperactive Ras Tumor (DHART) SPORE
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PROJECT 1: From Neurofibroma to MPNST: Models, Biology and Translation to Clinic
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Developmental and HyperActive Ras Tumor SPORE
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依托单位:
Project 1: Molecular and Genetic Features Across Mouse and Human Plexiform Neurofibromas to Inform Clinical Trials
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海外基金