THE ARF-P53 TUMOR SUPPRESSOR SIGNALING PATHWAY

ARF-P53 肿瘤抑制信号通路

• 批准号: 7369087
• 负责人: Michael G. Fried
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369087
• 关键词: ARF; P53; TUMOR; SUPPRESSOR; SIGNALING

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. The ARF-p53 tumor suppressor pathway is one of the cell?s major defenses against the stimulation of uncontrolled cell division induced by activated cellular and viral oncogene. ARF and/or p53 are mutated in over 70% of human cancers. The inappropriate activation of growth promoting cellular signaling pathways by oncogenes can result in the induction of ARF. The expression of ARF can activate p53 leading to apoptotic cell death or cell cycle arrest. The mechanisms by which the ARF-p53 pathway is regulated remains to be precisely elucidated. The expression of ARF can activate p53 leading to apoptotic cell death or cell cycle arrest. We have shown that the polyoma virus oncogene, PYMT, activates an ARF-induced p53 mediated block. We find that the polyoma virus small T-antigen, PYST, via its ability to bind to cellular protein phosphatase 2A (PP2A), can negate the ARF-induced block to cell division induced by PYMT. We intend to use the PY induction and inhibition of ARF signaling to p53 to better define this important tumor suppressor pathway. Our hypothesis is that the polyoma virus proteins are revealing an important new aspect of the ARF-p53 tumor suppressor signaling circuit, and we plan to use these viral proteins as tools to study its molecular basis. To better define the role of PYMT in activating ARF and as an oncogene, and to define the role of PYST in blocking ARF signaling to p53 we plan to characterize the proteins complexed to PYMT, PYST and members of the ARF-p53 signaling pathway. In the first instance proteins bound to TAP fusion constructs would be identified by Mass Spectrometry.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。 ARF-p53 肿瘤抑制途径是细胞针对激活的细胞和病毒癌基因诱导的不受控制的细胞分裂刺激的主要防御机制之一。超过 70% 的人类癌症中 ARF 和/或 p53 发生突变。癌基因对促生长细胞信号传导途径的不当激活可能导致 ARF 的诱导。 ARF 的表达可以激活 p53，导致细胞凋亡或细胞周期停滞。 ARF-p53 通路的调节机制仍有待精确阐明。 ARF 的表达可以激活 p53，导致细胞凋亡或细胞周期停滞。我们已经证明多瘤病毒癌基因 PYMT 可以激活 ARF 诱导的 p53 介导的阻断。我们发现多瘤病毒小 T 抗原 PYST 通过其与细胞蛋白磷酸酶 2A (PP2A) 结合的能力，可以消除 ARF 诱导的 PYMT 诱导的细胞分裂阻断。我们打算利用 PY 诱导和抑制 ARF 信号转导 p53 来更好地定义这一重要的肿瘤抑制途径。我们的假设是，多瘤病毒蛋白揭示了 ARF-p53 肿瘤抑制信号通路的一个重要的新方面，我们计划使用这些病毒蛋白作为工具来研究其分子基础。为了更好地确定 PYMT 在激活 ARF 和作为癌基因中的作用，并确定 PYST 在阻断 ARF 向 p53 信号传导中的作用，我们计划表征与 PYMT、PYST 和 ARF-p53 信号传导途径成员复合的蛋白质。首先，与 TAP 融合构建体结合的蛋白质将通过质谱法进行鉴定。