Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F

Nature. 1997 May 22;387(6631):422-6. doi: 10.1038/387422a0.

Abstract

Considerable evidence points to a role for G1 cyclin-dependent kinase (CDK) in allowing the accumulation of E2F transcription factor activity and induction of the S phase of the cell cycle. Numerous experiments have also demonstrated a critical role for both Myc and Ras activities in allowing cell-cycle progression. Here we show that inhibition of Ras activity blocks the normal growth-dependent activation of G1 CDK, prevents activation of the target genes of E2F, and results in cell-cycle arrest in G1. We also show that Ras is essential for entry into the S phase in Rb+/+ fibroblasts but not in Rb-/- fibroblasts, establishing a link between Ras and the G1 CDK/Rb/E2F pathway. However, although expression of Ras alone will not induce G1 CDK activity or S phase, coexpression of Ras with Myc allows the generation of cyclin E-dependent kinase activity and the induction of S phase, coincident with the loss of the p27 cyclin-dependent kinase inhibitor (CKI). These results suggest that Ras, along with the activation of additional pathways, is required for the generation of G1 CDK activity, and that activation of cyclin E-dependent kinase in particular depends on the cooperative action of Ras and Myc.

Publication types

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

MeSH terms

  • Animals
  • CDC2-CDC28 Kinases*
  • Carrier Proteins*
  • Cell Cycle Proteins*
  • Cell Line
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / metabolism*
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • Enzyme Inhibitors / metabolism
  • G1 Phase
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mutation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-myc / physiology*
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Retinoblastoma-Binding Protein 1
  • S Phase
  • Transcription Factor DP1
  • Transcription Factors
  • Tumor Suppressor Proteins*
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics
  • ras Proteins / physiology*

Substances

  • Arid4a protein, mouse
  • Carrier Proteins
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Cyclins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Enzyme Inhibitors
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins c-myc
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • ras Proteins