title: 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-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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yeh
authors.forename: Melissa
authors.initials: M
authors.lastname: Cunningham
authors.forename: Hugh
authors.initials: H
authors.lastname: Arnold
authors.forename: Dawn
authors.initials: D
authors.lastname: Chasse
authors.forename: Teresa
authors.initials: T
authors.lastname: Monteith
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ivaldi
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: P Todd
authors.initials: PT
authors.lastname: Stukenberg
authors.forename: Shirish
authors.initials: S
authors.lastname: Shenolikar
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Counter
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nevins
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Means
authors.forename: Rosalie
authors.initials: R
authors.lastname: Sears
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000235:genetics; D051381:Rats; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013912:Threonine / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016271:Proto-Oncogene Proteins c-myc; D013912:Threonine; D012694:Serine; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse