TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest

Cell. 1993 Sep 24;74(6):1009-20. doi: 10.1016/0092-8674(93)90723-4.

Abstract

Transforming growth factor beta 1 (TGF beta 1) causes G1 growth arrest and the accumulation of unphosphorylated retinoblastoma protein (Rb) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type G1 cyclins, can phosphorylate Rb in vitro, and at least one D-type cyclin, D2, directs the phosphorylation of Rb in vivo. Here we show that TGF beta 1 induces suppression of cdk4 synthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGF beta 1 resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGF beta 1 action, but its constitutive expression failed to override a TGF beta 1-induced G1 block. Hence, the TGF beta 1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGF beta 1-induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGF beta 1 growth suppression.

Publication types

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

MeSH terms

  • Animals
  • CDC2-CDC28 Kinases*
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Line
  • Clone Cells
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases*
  • Epithelium
  • Lung
  • Mink
  • Peptide Mapping
  • Phosphorylation
  • Protamine Kinase / metabolism
  • Protein Kinase Inhibitors
  • Protein Kinases / biosynthesis*
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / metabolism
  • Retinoblastoma Protein / metabolism
  • Transfection
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Retinoblastoma Protein
  • Transforming Growth Factor beta
  • Protein Kinases
  • Protamine Kinase
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases