The Role of Polyoma Small T in Regulating Cell Survival

多瘤小 T 在调节细胞存活中的作用

基本信息

批准号：
8233030
负责人：
BRIAN S SCHAFFHAUSEN
金额：
$ 56.17万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233030
关键词：
Address Apoptosis Apoptotic Binding Binding Proteins Biological Cell Death Cell Survival Cells Cessation of life Complement Complex Determination of Death Development Event Family Future Genes Genetic Goals Growth Growth Factor Growth and Development function Human Indium Knowledge Libraries Life Liver Malignant Neoplasms Mammalian Cell Modeling Molecular Mus Mutagenesis Names Oncogenes Outcome Papovaviridae Pathogenesis Pathway interactions Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Polyomavirus Principal Investigator Process Protein Isoforms Protein Tyrosine Kinase Protein p53 Protein phosphatase Proteins Proto-Oncogene Proteins c-akt RNA Interference Regulation Role Serum Signal Pathway Signal Transduction Simian virus 40 Site Stimulus System Testing Time Tissues Transducers Transgenic Organisms Tumor Suppressor Proteins Validation Viral Viral Oncogene Virus Withdrawal Work cancer cell cell growth cell killing insight killings member mouse polyomavirus mutant novel novel strategies prevent programs research study response transforming virus tumor tumorigenesis

项目摘要

Mechanisms of fundamental importance for tumor development and growth have been repeatedly uncovered by studying polyomaviruses. Tyrosine kinase activity, phosphoinositide 3-kinase (PI3K) activity and the tumor suppressor p53 were all discovered there. We have recently discovered that one viral oncogene, small T (PyST), can regulate survival in many different cells by causing or by preventing apoptosis. To switch between killing and promoting survival PyST uses the important cellular phosphatase PP2A. Which of the many PP2A species required for this life and death determination will be determined. One key target of PyST/PP2A action is the cellular kinase Akt. Since Akt is generally viewed as a pro-survival protein, the observation that it can be an apoptotic stimulus is quite provocative. PyST/PP2A modulates Akt phosphorylation on its T308 and S473 regulatory sites. The result is a differential alteration in the phosphorylation of Akt substrates. The role for Akt in general and for the asymmetric phosphorylation in particular will be confirmed. Akt substrates will be examined for their role in cell killing. It is likely that additional targets besides Akt are important for PyST killing. Non-biased screens will be performed to identify other pathways that are involved. The most likely direct targets would be ones that PyST binds and brings together with PP2A. New PyST binding proteins that might be required for cell killing will be identified. An advantage of murine polyomavirus is that signal transduction hypotheses can be tested in mice. We have uncovered a trick that will allow us to compare a virus that has PyST to one that does not. Whether PyST is required for virus growth and more importantly how it contributes to the polyoma tumor profile will be tested. The hypothesis that PyST/PP2A can function as a tumor suppressor in some tissues will be examined using liver as a model. The outcome of this work will be a fuller understanding of how PP2A and Akt participate in life and death decisions. It should illuminate new signal transduction mechanisms. In the future the knowledge gained here might allow us to decrease the survival of cancer cells selectively.

对肿瘤发展和生长的基本重要性的机制反复反复通过研究多瘤病毒而发现。酪氨酸激酶活性，磷酸肌醇3-激酶（PI3K）活性肿瘤抑制p53都在那里发现。我们最近发现一种病毒癌基因，小t（PYST），可以通过引起或防止许多不同细胞的生存凋亡。在杀戮和促进生存PYST之间切换使用重要的细胞磷酸酶 pp2a。将确定生命和死亡确定所需的许多PP2A物种中的哪一个。 PYST/PP2A作用的一个关键目标是细胞激酶AKT。由于AKT通常被视为促卵巢蛋白，观察到可能是凋亡刺激的观察是相当挑衅的。 PYST/PP2A 调节其T308和S473调节位点上的Akt磷酸化。结果是在 Akt底物的磷酸化。 AKT一般和不对称磷酸化的作用特别会确认。 AKT底物将检查其在细胞杀死中的作用。很可能除了AKT之外，其他目标对于PYST杀戮很重要。将执行非偏置屏幕确定其他所涉及的途径。最可能的直接目标是PYST绑定的目标和与PP2A一起融合。将确定细胞杀死可能需要的新PYST结合蛋白。鼠多瘤病毒的一个优点是可以在小鼠中测试信号转导假设。我们发现了一个技巧，它将使我们能够比较具有PYST的病毒与没有PYST的病毒。无论 PYST是病毒生长所必需的，更重要的是，它如何对多瘤肿瘤概况贡献测试。 PYST/PP2A可以在某些组织中充当肿瘤抑制剂的假设将是使用肝作为模型检查。这项工作的结果将是对PP2A和 AKT参与生死决策。它应照亮新的信号转导机制。在未来，这里获得的知识可能使我们能够选择性地降低癌细胞的存活率。