THE ARF-P53 TUMOR SUPPRESSOR SIGNALING PATHWAY

ARF-P53 肿瘤抑制信号通路

• 批准号: 7957391
• 负责人: Michael G. Fried
• 金额: $ 1.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957391
• 关键词: Affect; Antigen Targeting; Apoptotic; Binding; Biochemical; Biological; Catalytic Domain; Cell Cycle Arrest; Cell Death; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Defense Mechanisms; Funding; Grant; Growth; Human; Institution; Malignant Neoplasms; Mass Spectrum Analysis; Oncogenes; Pathway interactions; Phosphoric Monoester Hydrolases; Polyomavirus; Protein Binding; Protein p53; Protein phosphatase; Proteomics; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Small T Antigen; Source; TP53 gene; Tumor Suppressor Proteins; United States National Institutes of Health; Viral Tumor Antigens; cellular targeting; dimer; neoplastic cell; p53 Signaling Pathway; response; scaffold; sialosyl-T antigen

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Unscheduled growth signals stimulated by a number of activated oncogenes induce the ARF tumor suppressor protein. ARF can activate a p53 response resulting in cell cycle arrest or apoptotic cell death. The ARF-p53 tumor suppressor pathway is one of the cell's major defense mechanisms against cancer induced by activating oncogenes and is dysfunctional in a large number of human tumor cells. The ARF signaling pathway to p53 remains to be elucidated The polyoma virus (Py) activating oncogene, middle T-antigen (PyMT), induces ARF but none of the Py proteins bind to and inactivate p53. We have shown that the polyoma virus small T-antigen (PyST) targets the ARF signaling pathway to p53 so that p53 is not upregulated when ARF is activated. This inhibition of p53 induction requires the Protein Phosphatase 2A (PP2A) binding domain of PyST revealing a previously unrecognized role of PP2A in the ARF-p53 signaling pathway. The PP2A binding domain is required for PyST to substitute for the PP2A B regulatory subunit and bind to the PP2A A scaffolding subunit and C catalytic subunit dimer to form a new PP2A complex. Thus PyST through its interaction with PP2A is highlighting a new aspect of the important ARF-p53 tumor-suppressor pathway. We plan to use proteomic, biological and biochemical approaches to determine how PyST influences PP2A and PP2A cellular targets to affect this important cellular pathway.

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