The antineoplasic agent estramustine and the derivative estramustine-phosphate inhibit secretion of interleukin-3 in leukemic cells. Possible roles of MAPs |
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Authors: | Jorge Martínez Juan Francisco Santibáñez Clarisa Vial Ricardo B Maccioni |
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Institution: | (1) Instituto de Nutrición y Tecnología de Alimentos (INTA), Universidad de Chile, Casilla 138-11, Santiago, Chile;(2) International Center for Cancer and Developmental Biology (ICC), Universidad de Chile, Las Palmeras 3425, Nuñoa, Santiago, Chile;(3) Department of Biology, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Nuñoa, Santiago, Chile |
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Abstract: | The antineoplasic drug estramustine is an adduct of estradiol and nor-nitrogen mustard. It has been shown that this drug interferes with microtubule assembly, an effect mediated by estramustine interaction with microtubule-associated proteins (MAPS). In the present report we demonstrate that estramustine and the phosphorylated derivative of the drug, estramustine-phosphate, inhibit the secretion of interleukin-3 by WEHI-3B cells. These studies also show that the estramustine derivative specifically interacts with a MAPs component found in these cells, which exhibited characteristics ressembling those of tau protein isoforms. Western blots using a unique monoclonal antibody MTB6.22 that recognizes microtubule-binding domains on MAPs, indicated that this WEHI protein factor contained the antigenic determinant that are functionally significant for microtubule assembly. ELISA assays using this antibody, also showed a decrease in the levels of the immunoreactive protein in WEHI cells after treatment with EMP. Interestingly, it has been recently described that the action of estramustine-phosphate is mediated by a direct interaction with MAP-binding sites on the microtubule surface, which are recognized by the site-specific monoclonal antibody. These findings together with immuno-precipitation experiments using anti-interleukin-3 antibodies and the inhibitory effect of the estramustine derivative on WEHI secretion process suggest that this anti-mitotic agent may block IL-3 secretion by a mechanism involving its interaction with a tau-like MAPs component present in these cells. |
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Keywords: | leukemic cells interleukin-3 secretion estramustine estramustine-phosphate MAPs tau-like proteins |
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