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

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.

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Figure 1: Ubiquitinated c-Myc protein is phosphorylated on Thr 58, but not on Ser 62.
Figure 2: Accumulation of c-Myc is regulated by PP2A.
Figure 3: Ser 62 phosphate is a substrate for PP2A.
Figure 4: Pin1 interacts with c-Myc.
Figure 5: Accumulation of c-Myc is regulated by Pin1.
Figure 6: Pin1 is essential for normal control of c-Myc accumulation.
Figure 7: Small T antigen enhances the transactivation function of c-Myc.
Figure 8: Stabilized c-Myc cooperates with Ras and telomerase to transform human fibroblasts.

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Acknowledgements

We thank K. Culler for assistance in the preparation of the manuscript. R.S. was the recipient of a Howard Temin Award (CA 86957) that provided partial support for this work. Additional support was provided by start-up funds from Oregon Health & Sciences University and a grant from the NIH (CA100855) to R.S. Additional support came from the Howard Hughes Medical Institute (J.N.) and a grant from the NIH (CA-82845) to A.R.M.

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Correspondence to Rosalie Sears.

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Yeh, E., Cunningham, M., Arnold, H. et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 6, 308–318 (2004). https://doi.org/10.1038/ncb1110

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