Decrease in K-ras p21 and increase in Raf1 and activated Erk 1 and 2 in murine lung tumors initiated by N-nitrosodimethylamine and promoted by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Toxicol Appl Pharmacol. 2002 Feb 15;179(1):21-34. doi: 10.1006/taap.2001.9344.


Recent evidence suggests that K-ras protooncogene protein p21 may have a tumor-suppressive role in the context of development of lung adenocarcinoma. Levels of K-ras p21, raf-1, mitogen-activated protein kinases Erk 1 and 2, the phosphorylated-activated forms of Erk 1 and 2 (Erk 1P and 2P), and proliferating cell nuclear antigen (PCNA) were measured by immunoblotting in mouse lung tumors (5 to 9 mm in size) caused by N-nitrosodimethylamine (NDMA) and in control lungs. In tumors compared with normal lung, cell membrane-associated K-ras p21 was significantly decreased and cytosolic K-ras p21 increased. Total, membrane, and cytosolic raf-1 and Erk 1P and 2P were increased in tumors compared with normal lung. A single dose of 5 nmol/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given after NDMA resulted in a significant 2.4-fold increase in tumor multiplicity. A significantly greater decrease in membrane-associated K-ras p21 and increase in total and membrane associated raf-1 occurred in the NDMA/TCDD tumors compared with the NDMA-only tumors. PCNA levels increased in tumors, a finding confirmed by immunohistochemistry, and correlated with tumor size after NDMA/TCDD treatment but not after NDMA only. The increase in raf-1 in the tumors was confirmed by immunohistochemistry, which also revealed an increase in raf-1-positive alveolar macrophages specifically associating with tumors from the earliest stages. These results suggest a possible tumor-suppressive function for K-ras p21 in lung and a positive role for raf-1 and Erk 1/2 in lung tumorigenesis. TCDD may promote tumors by contributing to downregulation of K-ras and stimulation of raf-1.

MeSH terms

  • Animals
  • Carcinogens / toxicity*
  • DNA Mutational Analysis
  • Dimethylnitrosamine / toxicity*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Immunoblotting
  • Immunohistochemistry
  • Lung Neoplasms / chemically induced*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 1 / biosynthesis*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / biosynthesis*
  • Mitogen-Activated Protein Kinases / genetics
  • Oncogene Protein p21(ras) / biosynthesis*
  • Oncogene Protein p21(ras) / genetics
  • Polychlorinated Dibenzodioxins / toxicity*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proto-Oncogene Proteins c-raf / biosynthesis*
  • Proto-Oncogene Proteins c-raf / genetics


  • Carcinogens
  • Polychlorinated Dibenzodioxins
  • Proliferating Cell Nuclear Antigen
  • Proto-Oncogene Proteins c-raf
  • proto-oncogene protein v-RAF1, pig
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Oncogene Protein p21(ras)
  • Dimethylnitrosamine