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, 6 (4), 308-18

A Signalling Pathway Controlling c-Myc Degradation That Impacts Oncogenic Transformation of Human Cells

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A Signalling Pathway Controlling c-Myc Degradation That Impacts Oncogenic Transformation of Human Cells

Elizabeth Yeh et al. Nat Cell Biol.

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-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.

Comment in

  • PINning down the c-Myc oncoprotein.
    Dominguez-Sola D, Dalla-Favera R. Dominguez-Sola D, et al. Nat Cell Biol. 2004 Apr;6(4):288-9. doi: 10.1038/ncb0404-288. Nat Cell Biol. 2004. PMID: 15057241 No abstract available.

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