Nature Cell Biology
6, 308 - 318 (2004)
Published online: 14 March 2004; | doi:10.1038/ncb1110
A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cellsElizabeth Yeh1, Melissa Cunningham2, Hugh Arnold2, Dawn Chasse3, Teresa Monteith3, Giovanni Ivaldi1, William C. Hahn4, P. Todd Stukenberg5, Shirish Shenolikar1, Takafumi Uchida6, Christopher M. Counter1, Joseph R. Nevins3, Anthony R. Means1
& Rosalie Sears21
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. 2
Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR 97239, USA. 3
Department of Molecular Genetics and Microbiology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA. 4
Department of Medical Oncology and Medicine, Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. 5
Department of Biochemistry and Molecular Genetics, University of Virginia Medical School, Charlottesville, VA 22908, USA. 6
Institute of Development, Aging, and Cancer, Tohuku University, 4-1 Seiryo, Aoba, Sendai 980-8575, Japan.
Correspondence should be addressed to Rosalie Sears searsr@ohsu.eduThe 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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