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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

Authors

  • Yeh E
  • Cunningham M
  • Arnold H
  • Chasse D
  • Monteith T
  • Ivaldi G
  • Hahn WC
  • Stukenberg PT
  • Shenolikar S
  • Uchida T
  • Counter CM
  • Nevins JR
  • Means AR
  • Sears R

Journal

Nature cell biology

Publication Data

April 1, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA 100855
  • Agency: NCI NIH HHS, Id: CA 86957
  • Agency: NCI NIH HHS, Id: CA-82845

Mesh Terms

  • 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