Ras inhibition leads to transcriptional activation of p53 and down-regulation of Mdm2: two mechanisms that cooperatively increase p53 function in colon cancer cells

Cell Signal. 2004 Nov;16(11):1319-27. doi: 10.1016/j.cellsig.2004.04.003.

Abstract

Activated Ras, operating through the Raf/MEK/ERK pathway, is known to regulate transcription of both Mdm2 and its inhibitor p19ARF, resulting in opposing effects on the tumor suppressor protein p53. We show here that a decrease in Ras in SW480 cells induced either by the Ras inhibitor farnesylthiosalicylic acid (FTS) or by K-Ras antisense oligonucleotides, resulted in a similar increase in p53 protein. The increase in p53 was accompanied by an increase in p21(waf1/cip1) mRNA transcripts and protein. Consistent with the Ras/Raf/MEK/ERK-mediated control of Mdm2, treatment of SW480 cells with the Ras inhibitor FTS caused a marked (80%) decrease in Mdm2, which itself would account for the increase in p53. However, FTS also caused a 1.6-fold increase in p53 mRNA, indicative of a Ras-dependent mechanism that regulates p53 transcription. Thus, oncogenic Ras appears to attenuate p53 in SW480 cells by two independent regulatory mechanisms, the one leading to increased Mdm2-dependent p53 degradation and the other leading to a decrease in p53 transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / genetics
  • Carcinoma / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Down-Regulation / physiology
  • Enzyme Inhibitors / pharmacology
  • Genes, Regulator / drug effects
  • Genes, Regulator / physiology
  • Humans
  • Nuclear Proteins / metabolism*
  • Oligonucleotides, Antisense / pharmacology
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2
  • Transcriptional Activation / physiology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • ras Proteins