THE ARF-P53 TUMOR SUPPRESSOR SIGNALING PATHWAY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 ARF-P53抑癌通路是细胞抵抗由激活的细胞和病毒癌基因诱导的细胞分裂失控的主要防御途径之一。ARF和/或P53在超过70%的人类癌症中发生突变。癌基因对促生长细胞信号通路的不适当激活可导致ARF的发生。ARF的表达可激活P53，导致细胞凋亡或细胞周期停滞。ARF-P53通路的调控机制尚不清楚。ARF的表达可激活P53，导致细胞凋亡或细胞周期停滞。我们已经证明，多瘤病毒癌基因，PYMT，激活了ARF诱导的P53介导的阻断。我们发现，多瘤病毒小T抗原PYST通过与细胞蛋白磷酸酶2A(PP2A)结合，可以阻断PYMT诱导的ARF诱导的细胞分裂。我们打算利用PY对P53的ARF信号的诱导和抑制来更好地确定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新方面，我们计划利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，以及确定PYST在阻断ARF信号转导p53中的作用，我们计划对与PYMT、PYST和ARF-P53信号通路成员形成络合的蛋白质进行表征。在第一种情况下，结合到TAP融合结构的蛋白质将通过质谱学进行鉴定。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.