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

研究成果: Article査読

595 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)308-318
ページ数11
ジャーナルNature cell biology
6
4
DOI
出版ステータスPublished - 2004 4

ASJC Scopus subject areas

  • 細胞生物学

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