Diazonamide toxins reveal an unexpected function for ornithine delta-amino transferase in mitotic cell division.
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 delta-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.
Wang
Gelin
G
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
Shang
Libin
L
Burgett
Anthony W G
AW
Harran
Patrick G
PG
Wang
Xiaodong
X
D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D024101:Mitochondrial Proteins / Q000502:physiology; D008938:Mitosis / Q000187:drug effects*; D009865:Oocytes; D009953:Ornithine-Oxo-Acid Transaminase / Q000235:genetics / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology; D014981:Xenopus
D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D024101:Mitochondrial Proteins; D010080:Oxazoles; D034741:RNA, Small Interfering; D050257:Tubulin Modulators; C408862:diazonamide A; D009953:Ornithine-Oxo-Acid Transaminase