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Diazonamide toxins reveal an unexpected function for ornithine δ-amino transferase in mitotic cell division

Wang, Gelin, Shang, Libin, Burgett, Anthony W.G., Harran, Patrick G., Wang, Xiaodong
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.7 pp. 2068-2073
RNA interference, Xenopus, cell culture, cell death, cell division, drug therapy, drugs, eggs, humans, ornithine, osteosarcoma, toxins, uterine cervical neoplasms
We have studied a naturally occurring small-molecule antimitotic called diazonamide A. Diazonamide A is highly effective at blocking spindle assembly in mammalian cell culture and does so through a unique mechanism. A biotinylated form of diazonamide A affinity purifies ornithine δ-amino transferase (OAT), a mitochondrial enzyme, from HeLa cell and Xenopus egg extracts. In the latter system, the interaction between diazonamide A and OAT is regulated by RanGTP. We find that specific OAT knockdown in human cervical carcinoma and osteosarcoma cells by RNA interference blocks cell division and causes cell death, the effects largely phenocopying diazonamide A treatment in these cell lines. Our experiments reveal an unanticipated, paradoxical role for OAT in mitotic cell division and identify the protein as a target for chemotherapeutic drug development.