Study of Anti-Survival signals in NF1

NF1抗生存信号的研究

基本信息

批准号：
9108255
负责人：
CHANGYAN CHEN
金额：
$ 32.27万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108255
关键词：
Affect Anaphase Apoptosis Apoptotic Applications Grants Benign Binding Biological Cell Cycle Cell Cycle Checkpoint Cell Death Cell division Cells Complex Cyclins Cytokinesis Data Defect Development Disease Disease Outcome Ensure Event GTP Binding GTPase-Activating Proteins Genetic Genetic Techniques Goals Hereditary Malignant Neoplasm Human Individual Induction of Apoptosis Knowledge Link Longevity MAP Kinase Gene Mammalian Cell Mediating Mission Mitosis Mitotic Mitotic Checkpoint Molecular Mus Mutate Mutation NF1 gene NF1 tumor suppressor Nervous system structure Neurofibromatoses Neurofibromatosis 1 Neurofibromatosis Type 1 Protein Neurofibrosarcoma Oncogenic Pathway interactions Patients Phosphoric Monoester Hydrolases Population Process Protein Kinase Protein Kinase C Protein Kinase C Inhibitor Proteins Regulation Research Research Project Grants Role Schwann Cells Series Signal Pathway Signal Transduction Sister Chromatid Syndrome Testing Therapeutic Therapeutic Intervention Tumor Suppressor Genes United States National Institutes of Health Yeasts base cancer type chemical genetics cyclin B1 design in vivo inhibitor/antagonist knock-down loss of function mutation mouse model neoplastic cell novel novel therapeutic intervention outcome forecast research study treatment strategy ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant: Type 1 neurofibromatosis (NF1) is a prevalent familial cancer syndrome affecting certain numbers of human beings. The abnormal genetic locus in neurofibromatosis is Nf1, a tumor suppressor gene. The protein product of Nf1 (neurofibromin) is a GTPase-activating protein (GAP) that negatively regulates Ras signaling and expresses in a high level in Schwann cells that are the cell origin of NF1 disease. Loss-of- function mutations or deletion of Nf1 are responsible for hyper-activation of Ras pathway in NF1 patients. Our preliminary data demonstrated that mutated Nf1, together with the suppression of protein kinase C (PKC), is synthetically lethal, via the activation of the mitotic exit checkpoint. In this process, Plk1 was activated in a Chk1-dependent fashion. Through binding to cdc14B, Plk1 blocked its functions and further silenced Cdh1 activity, resulting in the increase of cyclin B1 stability and accumulation of Nf1 deficient neurofibromatosis cells in the M phase of the cell cycle. Importantly, the activation of this mitotic exit checkpoint coincided with the induction of apoptosis. In yeast and mammalian cells, mitotic exit involves an intricately ordered series of events, leading from the splitting of sister chromatids at anaphase onset to the completion of cell division by cytokinesis. If insults target late stages of mitosis, mitotic exit checkpoint would be activated and subsequently induce mitotic catastrophe to eliminate unwanted cells or terminates mitosis. Based on our preliminary data and our knowledge of the mitotic exit checkpoint, we hypothesize that Nf1 mutation, together with loss of PKC, is synthetically lethal, which is through the activation of the mitotic exit checkpoint. Identification of critical molecular events in this mitotic crisis will allow efficient therapeutic interventions of neurofibromatosis 1. To test this hypothesis, we will: 1) investigate the mechanism by which Plk1/cdc14B axis regulates the activation of this mitotic exit checkpoint in HMG- treated Nf1 deficient neurofibromatosis 1 cells; 2) investigate the role of Cdh1 in the mitotic exit checkpoint induced by PKC suppression in the Nf1 deficient cells; and 3) determine how Ras-mediated pathways trigger the mitotic exit checkpoint in HMG-treated Nf1 deficient cells and further induce apoptosis in vivo. Since Nf1 defect affects a large of human population and the poor prognosis for patients with advanced malignant peripheral nerve sheath tumor (MPNST) emphasize the urgent need for new chemotherapeutic approaches to treat this disease, the outcomes of this proposed study will have translational importance in the design of new therapeutic strategies to manipulate intracellular signaling and specifically re-direct the Nf1 deficient cells to undergo apoptosis, which is fully in accord with the central mission of NIH.