Abstract
Activation of the ARF-p53 tumor suppressor pathway is one of the cell's major defense mechanisms against cancer induced by oncogenes. The ARF-p53 pathway is dysfunctional in a high proportion of human cancers. The regulation of the ARF-p53 signaling pathway has not yet been well characterized. In this study polyoma virus (Py) is used as a tool to better define the ARF-p53 signaling pathway. Py middle T-antigen (PyMT) induces ARF, which consequently up-regulates p53. We show that Py small T-antigen (PyST) blocks ARF-mediated activation of p53. This inhibition requires the small T-antigen PP2A-interacting domain. Our results reveal a previously unrecognized role of PP2A in the modulation of the ARF-p53 tumor suppressor pathway.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Antigens, Polyomavirus Transforming / chemistry
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / physiology
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Cell Transformation, Viral
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DNA Damage
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Embryo, Mammalian / cytology
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Fibroblasts
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Fluorescent Antibody Technique, Direct
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Mutation
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Phosphoprotein Phosphatases / chemistry
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / physiology*
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Polyomavirus / genetics
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Polyomavirus / immunology
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Protein Structure, Tertiary
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Rats
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Signal Transduction / physiology
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Transfection
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Tumor Suppressor Protein p14ARF / antagonists & inhibitors
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Tumor Suppressor Protein p14ARF / metabolism*
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Tumor Suppressor Protein p53 / metabolism*
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Up-Regulation
Substances
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Antigens, Polyomavirus Transforming
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Phosphoprotein Phosphatases