Targeted disruption of the K-ras oncogene in an invasive colon cancer cell line down-regulates urokinase receptor expression and plasminogen-dependent proteolysis

Br J Cancer. 1999 Aug;80(12):1884-91. doi: 10.1038/sj.bjc.6690616.


The urokinase receptor, overexpressed in invasive colon cancer, promotes tumour cell invasion. Since K-Ras is activated in many colon cancers, we determined if urokinase receptor overexpression is a consequence of this activated oncogene. Accordingly, urokinase receptor expression was compared in HCT 116 colon cancer cells containing either a mutation-activated K-Ras or disrupted for this oncogene (by homologous recombination). HCT 116 cells containing the disrupted K-Ras oncogene expressed between 50 and 85% less urokinase receptor protein compared with the parental HCT 116 cells. Reduced urokinase receptor expression in cells containing the disrupted mutated K-Ras was not due to a physical impairment of the urokinase receptor gene since phorbol ester treatment was inductive for its expression. Constitutive urokinase receptor expression in HCT 116 cells required an intact AP-1 motif in the promoter (at -184) and electrophoretic mobility shifting assays indicated less c-Jun, JunD, c-Fos and Fra-1 bound to this motif in the K-Ras-disrupted cells. Since the urokinase receptor accelerates proteolysis, laminin degradation was compared in cells containing the mutation-activated and disrupted K-Ras oncogene. The latter cells displaying fewer urokinase receptors, degraded 80% less laminin. This is the first study to demonstrate a role for K-Ras as a regulator of the constitutive expression of the urokinase receptor.

Publication types

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

MeSH terms

  • Cell Nucleus / metabolism
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Genes, ras*
  • Humans
  • Laminin / metabolism
  • Mutagenesis
  • Plasminogen / metabolism*
  • Protein Biosynthesis
  • Receptors, Cell Surface / analysis
  • Receptors, Cell Surface / genetics*
  • Receptors, Urokinase Plasminogen Activator
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured


  • Laminin
  • PLAUR protein, human
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Plasminogen