Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2007 Feb 13;1047:2068-73. doi: 10.1073/pnas.0610832104.
Show Gene links
Show Anatomy links
Diazonamide toxins reveal an unexpected function for ornithine delta-amino transferase in mitotic cell division.
Wang G
,
Shang L
,
Burgett AW
,
Harran PG
,
Wang X
.
???displayArticle.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 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.
Blower,
A Rae1-containing ribonucleoprotein complex is required for mitotic spindle assembly.
2005, Pubmed,
Xenbase
Blower,
A Rae1-containing ribonucleoprotein complex is required for mitotic spindle assembly.
2005,
Pubmed
,
Xenbase
Brody,
Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences.
1992,
Pubmed
Cadoret,
Hepatomegaly in transgenic mice expressing an oncogenic form of beta-catenin.
2001,
Pubmed
Carazo-Salas,
Generation of GTP-bound Ran by RCC1 is required for chromatin-induced mitotic spindle formation.
1999,
Pubmed
,
Xenbase
Cruz-Monserrate,
Diazonamide A and a synthetic structural analog: disruptive effects on mitosis and cellular microtubules and analysis of their interactions with tubulin.
2003,
Pubmed
Desai,
Microtubule polymerization dynamics.
1997,
Pubmed
Ems-McClung,
Importin alpha/beta and Ran-GTP regulate XCTK2 microtubule binding through a bipartite nuclear localization signal.
2004,
Pubmed
,
Xenbase
Gruss,
Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity.
2001,
Pubmed
,
Xenbase
Harrington,
VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
2004,
Pubmed
Jiang,
Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway.
2003,
Pubmed
Jung,
Enzyme-activated irreversible inhibitors of L-ornithine:2-oxoacid aminotransferase. Demonstration of mechanistic features of the inhibition of ornithine aminotransferase by 4-aminohex-5-ynoic acid and gabaculine and correlation with in vivo activity.
1978,
Pubmed
Karsenti,
The mitotic spindle: a self-made machine.
2001,
Pubmed
,
Xenbase
Li,
Total Synthesis of Nominal Diazonamides-Part 2: On the True Structure and Origin of Natural Isolates Funding provided by the NIH (RO1-GM60591), the NSF (CAREER 9984282), the Howard Hughes Medical Institute (junior faculty support), the Robert A. Welch Foundation, and the Advanced Research Program of the Texas Higher Education Coordinating Board. We are grateful to Professor Michael Roth for his time, insight, and advice.
2001,
Pubmed
Li,
Total Synthesis of Nominal Diazonamides-Part 1: Convergent Preparation of the Structure Proposed for (-)-Diazonamide A Funding provided by the NIH (RO1-GM60591), the NSF (CAREER 9984282), the Howard Hughes Medical Institute (junior faculty support), the Robert A. Welch Foundation, and the Advanced Research Program of the Texas Higher Education Coordinating Board.
2001,
Pubmed
Mayer,
Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen.
1999,
Pubmed
,
Xenbase
STRECKER,
PURIFICATION AND PROPERTIES OF RAT LIVER ORNITHINE DELTA-TRANSAMINASE.
1965,
Pubmed
Seiler,
Ornithine aminotransferase, a potential target for the treatment of hyperammonemias.
2000,
Pubmed
Wang,
Mice lacking ornithine-delta-aminotransferase have paradoxical neonatal hypoornithinaemia and retinal degeneration.
1995,
Pubmed
Wilde,
Stimulation of microtubule aster formation and spindle assembly by the small GTPase Ran.
1999,
Pubmed
,
Xenbase
Williams,
Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity.
2007,
Pubmed
Wood,
Past and future of the mitotic spindle as an oncology target.
2001,
Pubmed
Zhong,
Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis.
2005,
Pubmed