A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells.
Journal Article (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
International Standard Serial Number (ISSN)
- 1465-7392
Digital Object Identifier (DOI)
- 10.1038/ncb1110
Language
- eng
Conference Location
- England