Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.
Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
Serrano
M
M
Cold Spring Harbor Laboratory, New York 11724, USA.
Lin
A W
AW
McCurrach
M E
ME
Beach
D
D
Lowe
S W
SW
D000818:Animals; D015415:Biomarkers; D015152:Blotting, Northern; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008817:Mice, Mutant Strains; D009857:Oncogenes / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014170:Transformation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics*
D015415:Biomarkers; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D018631:ras Proteins