Cancer may be the result of an unregulated or poorly regulated cell cycle that leads to uncontrolled proliferation. If the proliferation regulatory pathway is understood, then methods of intersecting the pathway by chemotherapy or prevention or other therapies can be designed. Using the modern technology of molecular biology, basic research findings about the regulation of cellular proliferation will be applied to the prevention, diagnosis and treatment of patients with lung cancer. by correlating the level of expression of proteins known to be involved in cell cycle regulation and mutagenicity with malignancy, markers of both diagnostic and prognostic value will be obtained. Overexpression could be used as a marker of this type. As shown from basic research studies on yeast, overexpression of Cdc7 kinase stimulates induced mutagenesis. Therefore, kinase overexpression may increase the probability of further induced mutations, some of which may be oncogenic. Patients who have elevated levels of these proteins and are exposed to environmental carcinogens/mutagens as are smokers would have a higher risk for lung cancer and would be then targeted for preventative measures. Towards this goal, mRNA, protein and enzymatic activities of the cdc2/Cdc28, cdk2/Eg1 and Cdc7 protein kinases will be determined initially in different lung cancer cell lines and later in normal, dysplastic (""""""""premalignant"""""""") and malignant lung tissues obtained from a central tissue bank core. Cyclin proteins which are regulators of these protein kinases will also be examined. New lung specific cyclins and the human homolog of the Cdc7 kinase will be cloned using a yeast complementation assay and PCR- technology and tested similarly. RB (retinoblastoma), a regulatory protein known to be important in small cell lung cancer and a substrate of cdc2/Cdc28 kinase, will be examined to determine if it is preferentially phosphorylated by cdk2/Eg1, cdc2/Cdc28 and Cdc7 kinases.
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