Ferbeyre, G., De Stanchina, E., Lin, A. W., Querido, E., McCurrach, M. E., Hannon, G. J., Lowe, S. W. (2002) Oncogenic ras and p53 cooperate to induce cellular senescence. Molecular and Cellular Biology, 22 (10). pp. 3497-3508. ISSN 02707306 (ISSN)
Abstract
Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53val735) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19ARF was required for this effect, since p53-/- ARF-/- double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19ARF on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53-/- mdm2-/- double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | gene product mitogen activated protein kinase protein p19 protein p53 allele animal cell article cell aging cell proliferation controlled study gene activation gene expression mitosis inhibition mouse nonhuman oncogene ras priority journal tumor suppressor gene Animals Cell Cycle Cell Fractionation Cells, Cultured Colony-Forming Units Assay Cyclin-Dependent Kinase Inhibitor p16 Embryo Enzyme Activation Fibroblasts Genes, p53 Genes, ras MAP Kinase Kinase 1 MAP Kinase Signaling System Mice Mice, Knockout Microscopy, Fluorescence Mitogen-Activated Protein Kinase Kinases Nuclear Proteins Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-mdm2 ras Proteins Temperature Tumor Suppressor Protein p14ARF Tumor Suppressor Protein p53 Animalia Murinae |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53 organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence |
| CSHL Authors: | |
| Communities: | CSHL labs > Hannon lab CSHL labs > Lowe lab |
| Depositing User: | Matt Covey |
| Date: | 2002 |
| Date Deposited: | 09 Jan 2013 16:56 |
| Last Modified: | 09 Jan 2013 16:56 |
| PMCID: | PMC133786 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/26468 |
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