THE ARF-P53 TUMOR SUPPRESSOR SIGNALING PATHWAY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 受多种癌基因激活的非程序性生长信号诱导ARF肿瘤抑制蛋白的表达。ARF可以激活P53反应，导致细胞周期停滞或细胞凋亡。ARF-P53抑癌通路是细胞通过激活癌基因来抵抗癌症的主要防御机制之一，在大量人类肿瘤细胞中存在功能障碍。多瘤病毒(Py)激活癌基因中间T抗原(PYMT)可诱导ARF，但Py蛋白不能与P53结合并使其失活。我们已经证明，多瘤病毒小T抗原(PYST)针对ARF信号通路到P53，因此当ARF被激活时，P53不会上调。这种对P53诱导的抑制需要PYST的蛋白磷酸酶2A(PP2A)结合域，揭示PP2A在ARF-P53信号通路中的先前未知的作用。PYST需要PP2A结合域来替代PP2A B调节亚基，并与PP2A支架亚基和C催化亚基二聚体结合，形成新的PP2A复合体。因此，PYST通过与PP2A的相互作用突出了重要的ARF-P53肿瘤抑制通路的一个新方面。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，从而影响这一重要的细胞途径。

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.