Polyoma virus disrupts ARF signaling to p53.
Polyoma virus (Py) differs from other small DNA tumor viruses in not encoding a protein that inactivates p53. The complete Py early region encoding the large T-antigen (PyLT), middle T-antigen (PyMT) and small T-antigen (PyST) will transform primary rodent cells and REF52 cells, but PyMT, the main Py oncogene, by itself will only transform these cells when p53 or ARF is inactivated. We have related Py oncogene cooperation with the effects of the Py T-antigens on the ARF-p53 signaling pathway. PyMT activates an ARF-induced p53-mediated block to cell division explaining the inability of PyMT alone to generate dividing transformed cells. In contrast, in REF52 cells transformed by the whole Py early region (PyREF52), ARF is upregulated but p53 is not activated. Thus PyLT and/or PyST negates the PyMT-induced ARF-mediated block to cell division by disrupting the signaling pathway from ARF to p53. Although there is no detectable interaction or co-localization of endogenous ARF (nucleoli) and MDM2 (nucleoplasm) in PyREF52 cells, expression of transfected ectopic ARF results in an MDM2/ARF interaction and sequestration of MDM2 into the nucleoli. Sequestration of MDM2 by ARF in the nucleoli is not essential for a p53 response in REF52 cells as activation of Raf in REF52Raf-ER cells results in an ARF-induced p53-mediated cell cycle block in the absence of a detectable ARF-MDM2 interaction. Py may provide new insights into the cellular ARF-p53 signaling pathway.
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Imperial Cancer Research Fund, PO Box 123, Lincoln's Inn Fields, London WC2A 3PX, UK.
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D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000502:physiology; D051381:Rats; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D000952:Antigens, Polyomavirus Transforming; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; D019908:Proto-Oncogene Proteins c-raf; D020823:ADP-Ribosylation Factor 1