期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 222, 期 1, 页码 111-121出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2007.04.006
关键词
acrylamide; glycidarnide; kinesin; microtubule; cell division; mitosis; meiosis
资金
- NIEHS NIH HHS [ES011223] Funding Source: Medline
The microtubule (MT) motor protein kinesin is a vital component of cells and organs expressing acrylamide (ACR) toxicity. As a mechanism of its potential carcinogenicity, we determined whether kinesins involved in cell division are inhibited by ACR similar to neuronal kinesin [Sickles, D.W., Brady, S.T., Testino, A.R., Friedman, M.A., and Wrenn, R.A. (1996). Direct effect of the neurotoxicant acrylamide on kinesin-based microtubule motility. Journal of Neuroscience Research 46, 7-17.] Kinesin-related genes were isolated from rat testes [Navolanic, P.M., and Sperry, A.O.. (2000). Identification of isoforms of a mitotic motor in mammalian spermatogenesis. Biology of Reproduction 62, 1360-1369.], their kinesin-like proteins expressed in bacteria using recombinant DNA techniques and the effects of ACR, glycidamide (GLY) and propionamide (a non-neurotoxic metabolite) on the function of two of the identified kinesin motors were tested. KIFC5A MT bundling activity, required for mitotic spindle formation, was measured in an MT-binding assay. Both ACR and GLY caused a similar concentration-dependent reduction in the binding of MT; concentrations of 100 mu M ACR or GLY reduced its activity by 60%. KRP2 MT disassembling activity was assayed using the quantity of tubulin disassembled from taxol-stabilized MT. Both ACR and GLY inhibited KRP2-induced NIT disassembly. GLY was substantially more potent; significant reductions Of 60% were achieved by 500 mu M a comparable inhibition by ACR required a 5 mu M concentration. Propionainide had no significant effect on either kinesin, except KRP2 at 10 mM. This is the first report of ACR inhibition of a mitotic/meiotic motor protein. ACR (or GLY) inhibition of kinesin may be air alternative mechanism to DNA adduction in the production of cell division defects and potential carcinogenicity. We conclude that ACR may act on multiple kinesin family members and produce toxicities in organs highly dependent on rnicrotubule-based functions. (c) 2007 Elsevier Inc. All rights reserved.
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