Diazonamide toxins reveal an unexpected function for ornithine δ-amino transferase in mitotic cell division
- 13 February 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 104 (7) , 2068-2073
- https://doi.org/10.1073/pnas.0610832104
Abstract
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.Keywords
This publication has 25 references indexed in Scilit:
- Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicityProceedings of the National Academy of Sciences, 2007
- Mule/ARF-BP1, a BH3-Only E3 Ubiquitin Ligase, Catalyzes the Polyubiquitination of Mcl-1 and Regulates ApoptosisCell, 2005
- A Rae1-Containing Ribonucleoprotein Complex Is Required for Mitotic Spindle AssemblyCell, 2005
- Importin α/β and Ran-GTP Regulate XCTK2 Microtubule Binding through a Bipartite Nuclear Localization SignalMolecular Biology of the Cell, 2004
- Diazonamide A and a Synthetic Structural Analog: Disruptive Effects on Mitosis and Cellular Microtubules and Analysis of Their Interactions with TubulinMolecular Pharmacology, 2003
- Distinctive Roles of PHAP Proteins and Prothymosin-α in a Death Regulatory PathwayScience, 2003
- The Mitotic Spindle: A Self-Made MachineScience, 2001
- Ran Induces Spindle Assembly by Reversing the Inhibitory Effect of Importin α on TPX2 ActivityCell, 2001
- Small Molecule Inhibitor of Mitotic Spindle Bipolarity Identified in a Phenotype-Based ScreenScience, 1999
- Isolation and structure determination of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona chinensisJournal of the American Chemical Society, 1991