In the present study, the authors performed a comparative sequence analysis of the K-ras gene. By comparing sequences from different mouse inbred strains, the authors have identified new nucleotide polymorphisms in the noncoding regions of mouse K-ras gene. They have also identified noncoding DNA segments evolutionarily conserved among the human, mouse, and rat. Computational analysis for transcription factor binding sites suggests that these polymorphic and conserved DNA sequences harbor potential cis-regulatory elements, which may contribute to the transcriptional regulation of the K-ras gene. Further studies on these potential regulatory sites may help to elucidate the fundamental mechanism underlying allele-specific activation and expression of K-ras gene in hybrid mouse lung tumors, which determines lung tumor susceptibility in mice.
"Studies employing computational analysis of cancerrelated sequence data have focused mainly on modelling and predicting the effect of mutations, usually at the level of individual nucleotides or codons in a single proto-oncogene or family of proto-oncogenes ( Wang et al. 2005). At the protein sequence level, bioinformatics and proteomics methods have been employed mainly to identify biomarkers for various types of cancers (Cho 2007). "
[Show abstract][Hide abstract] ABSTRACT: There is some evidence to suggest that peptide segments that are found rarely or never in the host proteome play a role in the immune response to disease-related proteins, both those derived from microbes and those derived from the host itself. We conjecture that this pattern may extend to human proto-oncoproteins. Our hypothesis in this study is that the frequency of rare peptide segments in sets of human proto-oncoproteins is significantly higher than in sets of control proteins, and we show that this is the case. Possible immunological implications of this observation are discussed.
Journal of The Royal Society Interface 11/2008; 6(30):123-7. DOI:10.1098/rsif.2008.0320 · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kras is the most frequently mutated ras family member in lung carcinomas, whereas Hras mutations are common in tumors from stratified epithelia such as the skin. Using a Hras knock-in mouse model, we demonstrate that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wild-type (WT) Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The two Kras isoforms undergo different post-translational modifications; therefore, these findings can have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.
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