Exploring a New Pathway Regulating Mitosis

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Molecules that disrupt cell division are employed broadly in the treatment of cancer. The mechanism is effective because cancer cells replicate more frequently than normal. However, systemic poisoning of this kind has limits and side effects accompanying the use of conventional anti-mitotics are well discussed. For the past three years, we have studied a new type of small molecule anti-mitotic - a natural product called diazonamide A. It is highly effective at blocking spindle assembly in cell culture, and does so through a unique mechanism. The compound targets a previously unknown proteolyzed form of the metabolic enzyme ornthine 5-amino transferase (OAT). This truncated protein functions in the spindle assembly process, acting in concert with mitotic machinery downstream of the small GTPase Ran. Diazonamide inhibits this unexpected second function of OAT. A particularly exciting aspect of this discovery is that OAT-mediated spindle assembly is not required for normal development, as evidenced by the viability of OAT-null mice. Redundancies must exist, although OAT clearly supports rapid cell division. When a synthetic diazonamide is dosed intravenously in nude mice, one can fully regress implanted human tumors without noticeable neutropenia or weight loss. This is unprecedented for a small molecule anti-mitotic. Our proposal aims to explore the origins of this selectivity and chart what appears to be a new regulatory pathway controlling onset of spindle assemble in higher eukaryotes. We propose a rigorous biochemical analysis of OAT functions in mitosis as well as studies of animals lacking the OAT gene product on genetic backgrounds predisposed to cancer. This research is relevant to public health because it could help understand how a new cancer drug works and guide its use in the clinic.