A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells.

Published

Journal Article

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.

Full Text

Duke Authors

Cited 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

Published Date

  • April 2004

Published In

Volume / Issue

  • 6 / 4

Start / End Page

  • 308 - 318

PubMed ID

  • 15048125

Pubmed Central ID

  • 15048125

International Standard Serial Number (ISSN)

  • 1465-7392

Digital Object Identifier (DOI)

  • 10.1038/ncb1110

Language

  • eng

Conference Location

  • England