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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 由许多激活的癌基因刺激的未定义的生长信号诱导了ARF肿瘤抑制蛋白。 ARF可以激活p53反应，从而导致细胞周期停滞或凋亡细胞死亡。 ARF-P53肿瘤抑制途径是该细胞通过激活癌基因引起的癌症的主要防御机制之一，并且在许多人类肿瘤细胞中功能障碍。 通往p53的ARF信号通路尚待阐明多瘤病毒（PY）激活癌基因，中间T抗原（PYMT）诱导ARF，但没有PY蛋白与py蛋白结合并失活p53。我们已经表明，多瘤病毒小型T抗原（PYST）靶向ARF信号通路到p53，因此当激活ARF时，p53不会上调。 P53诱导的这种抑制需要PYST的蛋白质磷酸酶2a（PP2A）结合结构域，揭示了PP2A在ARF-P53信号通路中的先前未识别的作用。 PYST需要PP2A结合结构域代替PP2A B调节亚基并与PP2A A支架亚基和C催化亚基二聚体结合以形成新的PP2A复合物。因此，PYST通过其与PP2A的相互作用突出了重要的ARF-P53肿瘤抑制途径的新方面。我们计划使用蛋白质组学，生物学和生化方法来确定PYST如何影响PP2A和PP2A细胞靶标，以影响这一重要的细胞途径。