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We are studying the eukaryotic cell cycle, in particular “cell cycle and cancer malignancy”, to understand the mechanism of chromosome instability during the cell cycle that is responsible for the malignancy of cancer cells. Chromosome instability is observed in cancer cells, but not in normal cells. Indeed, many human cancer cells exhibit mitotic defects, and the resulting chromosome instability has been shown to be a major cause of malignant tumor progression. Chromosome instability may result from abnormal responses to DNA damage and aberrant checkpoint regulation. Supporting this notion is that many human malignant tumors exhibit mitotic defects (such as centrosome aberrations, abnormal spindle formation, and chromosome missegregation), and the resulting chromosome instability has been shown to be a major cause of malignant tumor progression. Consequently, we are interested in the abnormal response mechanisms of cancer cells to environmental stresses, in particular their altered DNA damage checkpoint and regulation of centrosome maturation and chromosome segregation.

            In particular, we are focusing on functional analyses of the Ser/Thr kinases Lats (large tumor suppressor) and GAK (cyclin G-associated kinase). These kinases localize at the centrosome, regulate mitotic progression in response to DNA damage, and cause chromosome instability when their functions are disrupted. Both Lats (Lats1 and Lats2) and GAK form complexes with Mdm2. In turn, Mdm2 controls the stability of p53, which is a transcriptional regulator of the Lats2, cyclin G1 and Mdm2 genes. Thus, the Lats and GAK complexes have intimate correlation in their function (Fig. 1).

                In addition, to inhibit spontaneous metastasis and the growth of malignant tumors by inhibiting connexin 26, our laboratory has developed safe oleamide-derivative drugs that are associated with few side effects.