Mechanism of carcinogenesis by dysregulation of cell cycle via abnormal ubiquitin-mediated proteolysis

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In the present study, we focused on the APC/C ubiquitin ligase complex that is involved in the degradation of cell division-related proteins. We found that the speed of ubiquitylation process is dependent on the sequence of degradation domain. Moreover, we found that one of the APC/C substrate, geminin is phosphorylated at mitosis, and this phosphorylation leads to DNA synthesis by preventing from APC/C-mediated proteolysis at mitosis. We also found that knockdown of Emi1 which is an APC/C inhibitor enhances the sensitivity of anti-cancer drug. These findings indicate that ubiquitin-mediated proteolysis via APC/C ubiquitin ligase is essential to cell cycle regulation and suggest that abnormal regulation of APC/C-mediated proteolysis may be involved in carcinogenesis.