Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation.
The MYC and RAS oncogenes are frequently activated in cancer and, together, are sufficient to transform rodent cells. The basis for this cooperativity remains unclear. We found that although Ras interfered with Myc-induced apoptosis, Myc repressed Ras-induced senescence, together abrogating two main barriers of tumorigenesis. Inhibition of cellular senescence required phosphorylation of Myc at Ser-62 by cyclin E/cyclin-dependent kinase (Cdk) 2. Cdk2 interacted with Myc at promoters, where it affected Myc-dependent regulation of genes, including Bmi-1, p16, p21, and hTERT, which encode proteins known to control senescence. Repression of senescence by Myc was abrogated by the Cdk inhibitor p27Kip1, which is induced by antiproliferative signals like IFN-gamma or by pharmacological inhibitors of Cdk2 but not by inhibitors of other Cdks. In contrast, a phospho-mimicking Myc-S62D mutant was resistant to these manipulations. Inhibition of cyclin E/Cdk2 reversed the senescence-associated gene expression pattern imposed by Myc/cyclin E/Cdk2. This indicates a role of Cdk2 as a transcriptional cofactor and activator of the antisenescence function of Myc and provides mechanistic insight into the Myc-p27Kip1 antagonism. Finally, our findings highlight that pharmacological inhibition of Cdk2 activity is a potential therapeutical principle for cancer therapy, in particular for tumors with activated Myc or Ras.
Hydbring
Per
P
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Bahram
Fuad
F
Su
Yingtao
Y
Tronnersjö
Susanna
S
Högstrand
Kari
K
von der Lehr
Natalie
N
Sharifi
Hamid Reza
HR
Lilischkis
Richard
R
Hein
Nadine
N
Wu
Siqin
S
Vervoorts
Jörg
J
Henriksson
Marie
M
Grandien
Alf
A
Lüscher
Bernhard
B
Larsson
Lars-Gunnar
LG
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D019927:Cyclin E; D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012694:Serine; D007371:Interferon-gamma; D051357:Cyclin-Dependent Kinase 2; D018631:ras Proteins