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

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-My...

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Published in:	Nature cell biology Vol. 6; no. 4; pp. 308 - 318
Main Authors:	Sears, Rosalie, Yeh, Elizabeth, Cunningham, Melissa, Arnold, Hugh, Chasse, Dawn, Monteith, Teresa, Ivaldi, Giovanni, Hahn, William C, Stukenberg, P. Todd, Shenolikar, Shirish, Uchida, Takafumi, Counter, Christopher M, Nevins, Joseph R, Means, Anthony R
Format:	Journal Article
Language:	English
Published:	England Nature Publishing Group 01-04-2004
Subjects:	Amino Acid Sequence - genetics Animals Antigens, Polyomavirus Transforming - genetics Antigens, Polyomavirus Transforming - metabolism Cell Line Cell proliferation Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism DNA binding proteins Gene expression Genes, myc - genetics Humans Mice Mutation - genetics Neoplasms - genetics Neoplasms - metabolism NIMA-Interacting Peptidylprolyl Isomerase Peptidylprolyl Isomerase - genetics Peptidylprolyl Isomerase - metabolism Phosphoprotein Phosphatases - antagonists & inhibitors Phosphoprotein Phosphatases - genetics Phosphoprotein Phosphatases - metabolism Phosphorylation Physiological aspects Protein Phosphatase 2 Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Rats RNA Stability - genetics Serine - metabolism Signal Transduction - genetics Simian virus 40 Threonine - metabolism United States
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/ncb1110