Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras

Oncogene. 1999 Jan 7;18(1):87-92. doi: 10.1038/sj.onc.1202280.

Abstract

Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras Constitutive activation of the ras proto-oncogene is a frequent and early event in colon cancers, but the downstream nuclear targets are not fully understood. The Cdx-1 and Cdx-2 homeobox genes play crucial roles in intestinal cell proliferation and differentiation. In addition, Cdx-2 is a colonic tumour-suppressor gene, whereas Cdx-1 has oncogenic potential. Here, we show that constitutive activation of ras alters Cdx-1 and Cdx-2 expression in human colonic Caco-2 and HT-29 cells that harbour a normal ras proto-oncogene. Oncogenic ras downregulates Cdx-2 through activation of the PKC pathway and a decline in activity of the Cdx-2 promoter AP-1 site. This decline results from a PKC-dependent decrease in the relative expression of c-Jun, an activator of Cdx-2 transcription, compared to c-Fos, an inhibitor of Cdx-2. Unlike Cdx-2, Cdx-1 is upregulated by oncogenic ras and this effect is mediated by activation of the MEK1 pathway. These results indicate that oncogenic ras activation has opposite effects on Cdx-1 and Cdx-2 expression through distinct signalling pathways and they provide the first evidence for a functional link between ras activation and the downregulation of the Cdx-2 tumour-suppressor gene in colon cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Avian Proteins*
  • CDX2 Transcription Factor
  • Caco-2 Cells
  • Colonic Neoplasms
  • Cytoplasm
  • Down-Regulation*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor*
  • Genes, ras*
  • HT29 Cells
  • Homeodomain Proteins / genetics*
  • Humans
  • Isoenzymes / metabolism
  • Promoter Regions, Genetic
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • Response Elements
  • Signal Transduction
  • Trans-Activators
  • Transcription Factor AP-1 / metabolism

Substances

  • Avian Proteins
  • CDX1 protein, human
  • CDX2 Transcription Factor
  • Homeodomain Proteins
  • Isoenzymes
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Trans-Activators
  • Transcription Factor AP-1
  • protein kinase C gamma
  • Protein Kinase C