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-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.
Yeh
Elizabeth
E
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Cunningham
Melissa
M
Arnold
Hugh
H
Chasse
Dawn
D
Monteith
Teresa
T
Ivaldi
Giovanni
G
Hahn
William C
WC
Stukenberg
P Todd
PT
Shenolikar
Shirish
S
Uchida
Takafumi
T
Counter
Christopher M
CM
Nevins
Joseph R
JR
Means
Anthony R
AR
Sears
Rosalie
R
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
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