Abstract
The stability of c-Myc is regulated by multiple Ras effector pathways. Phosphorylation at Ser 62 stabilizes c-Myc, whereas subsequent phosphorylation at Thr 58 is required for its degradation. Here we show that Ser 62 is dephosphorylated by protein phosphatase 2A (PP2A) before ubiquitination of c-Myc, and that PP2A activity is regulated by the Pin1 prolyl isomerase. Furthermore, the absence of Pin1 or inhibition of PP2A stabilizes c-Myc. A stable c-Myc(T58A) mutant that cannot bind Pin1 or be dephosphorylated by PP2A replaces SV40 small T antigen in human cell transformation and tumorigenesis assays. Therefore, small T antigen, which inactivates PP2A, exerts its oncogenic potential by preventing dephosphorylation of c-Myc, resulting in c-Myc stabilization. Thus, Ras-dependent signalling cascades ensure transient and self-limiting accumulation of c-Myc, disruption of which contributes to human cell oncogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence / genetics
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / metabolism
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Cell Line
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Genes, myc / genetics*
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Humans
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Mice
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Mutation / genetics
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NIMA-Interacting Peptidylprolyl Isomerase
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Neoplasms / genetics
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Neoplasms / metabolism*
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Peptidylprolyl Isomerase / genetics
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Peptidylprolyl Isomerase / metabolism
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation
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Protein Phosphatase 2
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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RNA Stability / genetics
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Rats
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Serine / metabolism
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Signal Transduction / genetics
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Threonine / metabolism
Substances
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Antigens, Polyomavirus Transforming
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NIMA-Interacting Peptidylprolyl Isomerase
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Proto-Oncogene Proteins c-myc
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Threonine
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Serine
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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PIN1 protein, human
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Peptidylprolyl Isomerase
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Pin1 protein, mouse