K-ras gene polymorphisms are not the key to lung tumor susceptibility differences in mice
Abstract
Lung cancer remains the leading cause of cancer death in the United States. Despite an increased association between cigarette smoking and lung cancer, only 13% of chronic smokers develop lung cancer in their lifetime. Other factors (environmental, genetic, occupational) must contribute to the susceptibility for pulmonary neoplasia. Activation of the K-ras gene has been associated with approximately 35% of human adenocarcinomas and has been linked with susceptibility to the development of lung cancer in inbred mouse strains. The role of sequence differences within the promoter and intron regions on K-ras gene expression was investigated in two inbred mouse strains with different susceptibilities for lung cancer. DNA sequence analysis demonstrated minor base pair differences in the K-ras gene promoter region of the two strains. Transient expression assays revealed that neither the promoter nor the intronic region sequence differences had any effect on expression of the K-ras gene. The expression pattern of mRNA in whole lung, alveolar type II cell (the progenitor cell for murine lung tumors), or NNK-induced lung tumors from the two mouse strains was the same in ribonuclease protection assays. In addition, transient expression vectors containing the K-ras gene promoter and intronic regions from either mouse strain were transfected into three different lung tumor cell lines derived from mice with different lung tumor susceptibility to determine if trans-acting factors present within these cell lines may affect K-ras gene expression; K-ras gene expression was unaffected in any of these cell lines. The role of the repetitive element associated with K-ras gene mediated lung tumor susceptibility in mice was investigated in humans. This repetitive element was not detected in the human K-ras intron 2 by Southern analysis or by sequence analysis of 2,300 bp of the 5$\sp\prime$ region of the second intron of the human K-ras gene. These results suggest that factors other than increased K-ras gene expression are involved in modulating the clonal expansion of cells containing a mutated K-ras allele from A/J mice.
Degree
Ph.D.
Advisors
Belinsky, Purdue University.
Subject Area
Molecular biology|Genetics|Oncology
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