THE ARF-P53 TUMOR SUPPRESSOR SIGNALING PATHWAY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。ARF-p53肿瘤抑制通路是细胞凋亡的重要途径之一。主要防御由激活的细胞和病毒癌基因诱导的不受控制的细胞分裂的刺激。ARF和/或p53在超过70%的人类癌症中突变。癌基因对促生长细胞信号通路的不当激活可导致ARF的诱导。ARF的表达可激活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的表达可激活p53，导致细胞凋亡或细胞周期停滞。我们已经表明，多瘤病毒癌基因，PYMT，激活ARF诱导的p53介导的阻滞。我们发现，多瘤病毒小T抗原，PYST，通过其结合细胞蛋白磷酸酶2A（PP 2A）的能力，可以否定由PYMT诱导的ARF诱导的细胞分裂阻滞。我们打算利用PY诱导和抑制ARF信号转导至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研究其分子基础的工具。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信号传导至p53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。在第一种情况下，与TAP融合构建体结合的蛋白质将通过质谱法鉴定。

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.