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

Research output: Contribution to journalArticlepeer-review

550 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)308-318
Number of pages11
JournalNature cell biology
Volume6
Issue number4
DOIs
Publication statusPublished - 2004 Apr 1

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells'. Together they form a unique fingerprint.

Cite this