Interdisciplinary Training

Karen Spratt

Analysis of Ras Induced Pathways During Lung Tumor Progression In Vivo

Human and mouse lung adenocarcinomas harbor a mutation in the K-ras proto-oncogene which renders the protein constitutively active. Ras has been implicated in signal transduction pathways culminating in a cellular response to proliferate or differentiate. However, it is not known how these signaling pathways contribute to ras-driven tumor progression in vivo. We will take advantage of the fact that the 20-50 fold difference in lung tumor susceptibility between the sensistive A/J mouse strain and the resistant C57Bl6 strain is due to a polymorphism in the second intron of Kras. This polymorphism is thought to influence expression levels and hence the phenotypic penetrance of Kras mutations. We will determine if different ras-related signaling pathways are activated in tumors with K-ras mutations from A/J vs. C57BL6 mice. Signaling effector differences observed between the strains will provide a biochemical explanation for the differences in lung tumor susceptibility observed. This will highlight which signaling pathways from ras are critical for lung tumor development in vivo.

In vitro studies have shown that activated ras can lead to upregulation of the tumor suppressor p53, leading to cell cycle arrest, premature senescence, or apoptosis. This has led to the idea that loss of p53 function is necessary for ras-induced transformation. This has not yet been demonstrated during solid tumor development in vivo. Paradoxically, p53 is not upregulated in murine lung tumors, nor are mutations in the p53 gene found, despite the presence of activating K-ras mutations. We will determine which components of the signaling cascade between active ras and p53 upregulation are inoperative in murine lung tumors. This will provide a mechanistic explanation for the lack of a role of p53 in murine lung tumorigenesis and will contribute to an understanding of the interplay between activated ras and p53 during tumor development.

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