A temporal and biochemical link between growth factor-activated MAP kinases, cyclin D1 induction and cell cycle entry.
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.
Lavoie
J N
JN
Centre de Biochimie-CNRS, Université de Nice, France.
Rivard
N
N
L'Allemain
G
G
Pouysségur
J
J
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D006133:Growth Substances; D008869:Microtubule-Associated Proteins; D008934:Mitogens; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases