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Heterozygous inactivation of TGF-beta 1 increases the susceptibility to chemically induced mouse lung tumorigenesis independently of mutational activation of K-ras

  1. Author:
    McKenna, I. M.
    Ramakrishna, G.
    Diwan, B. A.
    Kang, Y.
    Shiao, Y. H.
    Wakefield, L. M.
    Powell, D. A.
    Anderson, L. M.
    Jakowlew, S. B.

  2. Author Address

    NCI, Div Canc Biol, Lab Cell Regulat & Carcinogenesis, 6130 Execut Blvd, EPN 5000, Bethesda, MD 20892 USA. US EPA, Off Pollut Prevent & Tox Subst, Washington, DC 20460 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Med Branch, Dept Cell & Canc Biol, NCI, Rockville, MD 20850 USA. NCI, Comp & Stat Serv, Data Management Serv, Frederick, MD 21702 USA. McKenna IM NCI, Div Canc Biol, Lab Cell Regulat & Carcinogenesis, 6130 Execut Blvd, EPN 5000, Bethesda, MD 20892 USA.
    1. Year: 2001
  2. Journal: Toxicology Letters
    1. 123
    2. 2-3
    3. Pages: 151-158
  4. Type of Article: Article
  1. Abstract:

    Mice heterozygous for deletion of the transforming growth factor beta1 (TGF-beta1) gene show an enhanced rate of lung tumorigenesis following carcinogen treatment. Since the growth inhibitory activity of TGF-beta1 in epithelial cells is associated with K-ras p21, and K-ras mutations commonly occur in chemically-induced mouse lung tumors, we postulated that tumors in heterozygous TGF-beta1 mice might be more likely to have K-ras mutations compared with tumors in wildtype TGF-beta1 mice. Urethane-induced lung tumors in AJBL6 TGF-beta1 + / - and + / + mice were examined for K-ras mutations by polymerase chain reaction/single strand conformation polymorphism analysis and sequencing. Mutation frequencies were similar in both genotypes: 12/18 + / - tumors (67%) and 10/16 + / + tumors (62%). Mutations occurred in 80% + / - and 75% + / + carcinomas, but in only 50% of the adenomas of both TGF-P I genotypes. Codon 61 A --> G transition mutations were predominant, occurring in 61% + / - and 44% + / + tumors. Three + / - (17%) and three + / + (19%) tumors showed codon 12 mutations, mostly G -->A transitions. Two + tumors had both codon 61 and codon 12 mutations. Interestingly, carcinomas with mutations in codon 61 were larger than those with codon 12 changes. It appears that the mechanism of enhanced susceptibility of TGF-beta1 + / - mice to urethane-induced lung carcinogenesis does not involve selective development of tumors with K-ras mutations. Published by Elsevier Science Ireland Ltd.

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