| Research Abstract |
To analyze the genes controlling radiation-induced chromosome aberration and chromosomal instability which is commonly found in human cancer cells, we have isolated several mammalian homologues of the yeast mitotic checkpoint genes and examined their biochemical properties using human tumor cell lines and cancerous tissues.
Recently, we isolated a rat gene encoding a novel protein serine/threonine protein kinase, AIM-1, which is a key regulator of the onset of cytokinesis during mitosis. In this study, we cloned two human kinase genes involved in mitosis, the human genes for a functional homologue of rat AIM-1 and for serine/threoine kinase 15, STK15 which is also known as Aik and aurora2. In human tumor cell lines with multinuclear cells, AIM-1 was found to be overexpressed, and the exogenously induced overexpression of wild-type AIM-1 in human diploid fibroblasts caused multinuclearity and aneuploidy. Thus, AIM-1 is considered to play an important role in the regulation of mitotic progression. Interestingly, the AIM-1 and STK15 were overexpressed in human colorectal tumors, but only the expression levels of AIM-1 were increased with their grades of malignancy, indicating that AIM-1 expression may be involved in tumor progression.
Recent studies indicated that Ipl1/aurora family of protein kinase had an activity of site-specific phosphorylation of histone H3 at serine 10. We examined the levels of histone H3 phosphorylation in various human cancer cell lines using an antibody against phosphorylated histone H3, and then found that hitone H3 was hyperphosphorylated during mitosis and the amount of phophorylated histone H3 was much higher in aneuploid cancer cell lines displaying an overexpression of AIM-1 than in normal human diploid fibroblasts. These data indicate that AIM-1 is a regulator of mitotic chickpoints and that hyperphosphorylation of histone H3 causes chromosomal instability in AIM-1-overexpressing cancer cells.
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