Podophyllotoxin and nocodazole counter the effect of IKP104 on tubulin decay

Veena Prasad, Asish Ray Chaudhuri, Matthew Curcio, Isao Tomita, Fukutaro Mizuhashi, Kyoji Murata, Richard F. Ludueña

Resultado de la investigación: Articlerevisión exhaustiva

3 Citas (Scopus)

Resumen

Tubulin, the subunit protein of microtubules, undergoes a time-dependent loss of functional properties known as decay. We have previously shown that the drug 2-(4-fluorophenyl)-1-(2-chloro-3,5-dimethoxyphenyl)-3-methyl-6- phenyl-4(1H)-pyridinone (IKP104) accelerates decay, but that in the presence of colchicine, IKP104 becomes a stabilizer of tubulin. To see if this is due to conformational effects specific to colchicine or simply to occupancy at the colchicine site, we examined the effects of nocodazole and podophyllotoxin, two well-known competitive inhibitors of colchicine for binding to tubulin, on IKP104's acceleration of decay. We found that podophyllotoxin abolished IKP104's accelerating effect and, like colchicine, turned it into a stabilizer of tubulin. Nocodazole's effects were similar to those of podophyllotoxin and colchicine, in that it abolished IKP104-induced enhancement of decay; however, in the presence of nocodazole, IKP104 caused little or no stabilization of tubulin. Since colchicine, nocodazole, and podophyllotoxin have very different interactions with tubulin, but all inhibit the IKP104-induced enhancement of decay, our findings suggest that this inhibition arises from occupancy of the colchicine site rather than from a direct conformational effect of these two drugs.

Idioma originalEnglish (US)
Páginas (desde-hasta)663-668
Número de páginas6
PublicaciónJournal of Protein Chemistry
Volumen17
N.º7
DOI
EstadoPublished - oct. 1998
Publicado de forma externa

ASJC Scopus subject areas

  • Biochemistry

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