THE ARF-P53 TUMOR SUPPRESSOR SIGNALING PATHWAY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 由许多激活的癌基因刺激的非程序性生长信号诱导ARF肿瘤抑制蛋白。ARF可以激活p53反应，导致细胞周期停滞或凋亡性细胞死亡。ARF-p53肿瘤抑制通路是细胞对由激活癌基因诱导的癌症的主要防御机制之一，并且在大量人类肿瘤细胞中功能失调。 P53的ARF信号通路仍有待阐明。多瘤病毒（Py）激活癌基因，中间T抗原（PyMT），诱导ARF，但没有Py蛋白结合和抑制p53。我们已经表明，多瘤病毒小T抗原（PyST）的ARF信号通路的p53的目标，使p53不上调时，ARF被激活。这种p53诱导的抑制需要PyST的蛋白磷酸酶2A（PP 2A）结合结构域，揭示了PP 2A在ARF-p53信号通路中以前未被认识的作用。PP 2A结合结构域是PyST取代PP 2A B调节亚基并与PP 2A A支架亚基和C催化亚基二聚体结合形成新的PP 2A复合物所必需的。因此，PyST通过其与PP 2A的相互作用突出了重要的ARF-p53肿瘤抑制途径的一个新方面。我们计划使用蛋白质组学，生物学和生物化学方法来确定PyST如何影响PP 2A和PP 2A细胞靶点来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.