Abstract
Cell cycle re-entry requires the growth factor-stimulation of at least two distinct classes of protein kinases: (i) the p42/p44 MAP kinases activated by the Ras > Raf > MKK cascade and (ii) the G1 cyclin-dependent protein kinases (CDKs). Specific inactivation of either class of kinase arrests fibroblasts in G1. Growth factors promote nuclear translocation and persistent activation of p42/p44 MAP kinases during the entire G0/G1 period. Here, we demonstrate that induction of cyclin D1, and therefore cdk4/6 activity associated with, is positively controlled by the p42/p44 MAP kinase cascade whereas the parallel cytokines/stress-activated p38MAP kinase cascade is antagonistic. Finally, using an antisense approach we demonstrate that p27Kip1 plays a key role in setting the growth factor-dependency of the G0 state.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Cycle / genetics
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Cell Cycle / physiology*
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Cell Cycle Proteins*
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Cyclin D1 / biosynthesis*
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Cyclin D1 / genetics
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism
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Enzyme Activation
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Growth Substances / metabolism*
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Humans
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Microtubule-Associated Proteins / metabolism
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Mitogens / pharmacology
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Promoter Regions, Genetic
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Signal Transduction
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Tumor Suppressor Proteins*
Substances
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Cell Cycle Proteins
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Growth Substances
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Microtubule-Associated Proteins
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Mitogens
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Tumor Suppressor Proteins
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Cyclin D1
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Cyclin-Dependent Kinase Inhibitor p27
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Calcium-Calmodulin-Dependent Protein Kinases
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Cyclin-Dependent Kinases