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Nature Cell Biology 6, 308–318 (1 April 2004) | doi:10.1038/ncb1110

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

Elizabeth Yeh , Melissa Cunningham , Hugh Arnold , Dawn Chasse , Teresa Monteith , Giovanni Ivaldi , William C. Hahn , P. Todd Stukenberg , Shirish Shenolikar , Takafumi Uchida , Christopher M. Counter , Joseph R. Nevins , Anthony R. Means & Rosalie Sears

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-MycT58A 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.