Abstract
The cell-cycle inhibitor p21 is upregulated during senescence and upon induction of senescence-like arrest by oncogenic Ras. We have used primary fibroblasts derived from p21-null mice to evaluate the role of p21 in these processes. We find that primary p21-/- cells enter senescence and have a lifespan similar to wild-type cells. Upon immortalization, most wild-type and p21-/- cultures acquire alterations in either p53 or p16INK4a, further indicating that p21-deficiency is not sufficient by itself to allow immortalization. Primary p21-/- cells, like wild-type cells, respond to oncogenic Ras by accumulating p53 and p16INK4a, and by decreasing their proliferation rate. In agreement with this, p21-/- cells are refractory to neoplasic transformation by oncogenic Ras when compared to p53-/- cells. We conclude that, in murine fibroblasts, p21 is not essential neither for senescence nor for preventing neoplasic transformation by oncogenic Ras.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Cell Cycle
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Cell Division
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Cell Line, Transformed
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Cell Transformation, Neoplastic* / genetics
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Cells, Cultured
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Cellular Senescence*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / deficiency
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Cyclins / genetics
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Cyclins / physiology*
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Doxorubicin / pharmacology
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Fibroblasts / cytology*
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Deletion
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Gene Expression / drug effects
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Mice
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Mice, Knockout
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Oncogene Protein p21(ras) / genetics
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Oncogene Protein p21(ras) / metabolism*
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Serial Passage
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Transduction, Genetic
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Tumor Suppressor Protein p53
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Doxorubicin
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Oncogene Protein p21(ras)