A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells
| Autor: | William C. Hahn, Rosalie C. Sears, Christopher M. Counter, Joseph R. Nevins, Shirish Shenolikar, Takafumi Uchida, Giovanni Ivaldi, Anthony R. Means, Melissa Cunningham, Elizabeth S. Yeh, Dawn Chasse, Teresa Monteith, P. Todd Stukenberg, Hugh Arnold |
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| Rok vydání: | 2004 |
| Předmět: |
Threonine
Antigens Polyomavirus Transforming RNA Stability Genes myc macromolecular substances Biology environment and public health Cell Line Proto-Oncogene Proteins c-myc Dephosphorylation Mice Neoplasms Phosphoprotein Phosphatases Serine Prolyl isomerase Animals Humans Amino Acid Sequence Protein Phosphatase 2 Phosphorylation Effector Cell Biology Protein phosphatase 2 Peptidylprolyl Isomerase Cell cycle Molecular biology Rats Cell biology NIMA-Interacting Peptidylprolyl Isomerase enzymes and coenzymes (carbohydrates) Cell Transformation Neoplastic Mutation PIN1 Signal transduction Signal Transduction |
| Zdroj: | Nature Cell Biology. 6:308-318 |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/ncb1110 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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