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F-box ubiquitin ligases destabilize neurofibromin

F-box 泛素连接酶破坏神经纤维蛋白的稳定性

基本信息

批准号：
10249088
负责人：
David W Clapp
金额：
$ 34.45万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249088
关键词：
Affect Alleles Automobile Driving B-Lymphocytes Biochemical Bone Marrow Bone Marrow Transplantation Cells Chemotaxis Chemotherapy and/or radiation Clinical Complex F Box Domain F-Box Proteins Family GTPase-Activating Proteins Genes Genetic Genetically Engineered Mouse Genome Genomic approach Glioblastoma Growth Factor Hematopoietic Hematopoietic System Hematopoietic stem cells Heterogeneity Human Human Genetics Individual Inflammatory Knockout Mice Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic Melanoma Morbidity - disease rate Mus Mutation Myeloid Cells NF1 gene Neurofibromatoses Neurofibromatosis 1 Non-Malignant Pathologic Pathway interactions Patients Pharmacological Treatment Phase II Clinical Trials Phenotype Phosphorylation Phosphotransferases Plexiform Neurofibroma Pre-Clinical Model Preparation Process Proteins RNA interference screen Radiation therapy Regulation Resistance Signal Pathway Signal Transduction Small Interfering RNA Specificity Stem Cell Factor Syndrome Testing Tissues Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitin Ubiquitination Work cancer predisposition clinically significant drug discovery functional genomics in vivo innovation insight interdisciplinary approach kinase inhibitor mast cell mortality multicatalytic endopeptidase complex novel patient response premalignant prevent recruit response screening success therapeutic candidate therapeutic target tumor tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

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.

项目摘要/摘要