A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells.
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.
Pubmed ID: 15048125 RIS Download
Amino Acid Sequence | Animals | Antigens, Polyomavirus Transforming | Cell Line | Cell Transformation, Neoplastic | Genes, myc | Humans | Mice | Mutation | Neoplasms | Peptidylprolyl Isomerase | Phosphoprotein Phosphatases | Phosphorylation | Protein Phosphatase 2 | Proto-Oncogene Proteins c-myc | RNA Stability | Rats | Serine | Signal Transduction | Threonine