A Temporal and Biochemical Link Between Growth Factor-Activated MAP Kinases, Cyclin D1 Induction and Cell Cycle Entry

Prog Cell Cycle Res. 1996;2:49-58. doi: 10.1007/978-1-4615-5873-6_5.


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

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cell Cycle Proteins*
  • Cyclin D1 / biosynthesis*
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism
  • Enzyme Activation
  • Growth Substances / metabolism*
  • Humans
  • Microtubule-Associated Proteins / metabolism
  • Mitogens / pharmacology
  • Promoter Regions, Genetic
  • Signal Transduction
  • Tumor Suppressor Proteins*


  • Cell Cycle Proteins
  • Growth Substances
  • Microtubule-Associated Proteins
  • Mitogens
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cyclin-Dependent Kinases