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

doi:10.1006/taap.2001.9344

Toxicology and Applied Pharmacology

Volume 179, Issue 1, 15 February 2002, Pages 21-34

https://doi.org/10.1006/taap.2001.9344 Get rights and content

Abstract

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.

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¹: Current address: Centre For DNA Fingerprinting and Diagnostics, ECIL Road, Hyderabad-500 076, A.P. India.

²: To whom correspondence should be addressed at NCI–Frederick, Bldg. 538, Frederick, MD 21702-1201. Fax: 301-846-5946; E-mail: [email protected].

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Regular ArticleDecrease 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

Abstract

Biochem. Pharmacol.

Biochem. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Biochem. Pharmacol.

Cytokine Growth Factor Rev.

Fundam. Appl. Toxicol.

Trends Cell Biol.

J. Biol. Chem.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced decrease in the fluidity of rat liver membranes

Xenobiotica

Macrophage infiltration in human non-small-cell lung cancer: The role of CC chemokines

Cancer Immunol. Immunother.

Differential enzyme induction of mouse liver and lung following a single low or high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

J. Biochem. Toxicol.

Promotion of N-nitrosodimethylamine-initiated mouse lung tumors following single or multiple low dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Carcinogenesis

Ras oncogenes in human cancer: A review

Cancer Res.

Tissue specific expression of the rat Ah-receptor and ARNT mRNAs

Nucleic Acids Res.

Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion

Food Addit. Contam.

Heterogeneous response patterns of alveolar macrophages from patients with lung cancer by stimulation with interferon-gamma

Jpn. J. Clin. Oncol.

Genetic alterations in mouse lung tumors: Implications for cancer chemoprevention

J. Cell. Biochem. Suppl.

Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells

Carcinogenesis

Nitric oxide-mediated cytotoxic effects of alveolar macrophages on transformed lung epithelial cells are independent of the beta 2 integrin-mediated intercellular adhesion

Immunology

Dioxin dilemmas

J. Natl. Cancer Inst.

Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors

Oncogene

Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins

Cell Biol. Toxicol.

Reduction in transforming growth factor-beta type II receptor in mouse lung carcinogenesis

Mol. Carcinog.

Enhanced tumorigenesis and reduced transforming growth factor-beta type II receptor in lung tumors from mice with reduced gene dosage of transforming growth factor-beta1

Mol. Carcinog.

Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-type protein

Cell Growth Differ.

Partial regression in primary carcinoma of the lung: Does it occur?

Histopathology

Regular Article
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