HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 30, 21592-21597, July 27, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/30/21592    most recent M608505200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Thevissen, K. Articles by François, I. E. J. A. Search for Related Content PubMed PubMed Citation Articles by Thevissen, K. Articles by François, I. E. J. A. Social Bookmarking                      What's this?

Miconazole Induces Changes in Actin Cytoskeleton prior to Reactive Oxygen Species Induction in Yeast^*

Karin Thevissen¹, Kathryn R. Ayscough², An M. Aerts³, Wei Du, Katrijn De Brucker, Els M. K. Meert, Jannie Ausma^¶, Marcel Borgers^¶, Bruno P. A. Cammue⁴, and Isabelle E. J. A. Franois⁵

From the Centre of Microbial and Plant Genetics, Katholieke Universiteit Leuven, 3001 Heverlee, Belgium, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, United Kingdom, and ^¶BarrierTherapeutics nv, 2440 Geel, Belgium

The antifungal compound miconazole inhibits ergosterol biosynthesis and induces reactive oxygen species (ROS) in susceptible yeast species. To further uncover the mechanism of miconazole antifungal action and tolerance mechanisms, we screened the complete set of haploid Saccharomyces cerevisiae gene deletion mutants for mutants with an altered miconazole sensitivity phenotype. We identified 29 S. cerevisiae genes, which when deleted conferred at least 4-fold hypersensitivity to miconazole. Major functional groups encode proteins involved in tryptophan biosynthesis, membrane trafficking including endocytosis, regulation of actin cytoskeleton, and gene expression. With respect to the antifungal activity of miconazole, we demonstrate an antagonism with tryptophan and a synergy with a yeast endocytosis inhibitor. Because actin dynamics and induction of ROS are linked in yeast, we further focused on miconazole-mediated changes in actin cytoskeleton organization. In this respect, we demonstrate that miconazole induces changes in the actin cytoskeleton, indicative of increased filament stability, prior to ROS induction. These data provide novel mechanistic insights in the mode of action of a ROS-inducing azole.

Received for publication, September 5, 2006 , and in revised form, May 10, 2007.

^* This work was supported in part by a grant from Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen (IWT-Vlaanderen) (030023). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a postdoctoral fellowship from Katholieke Universiteit Leuven (Industrial Research Fellow).

² A senior non-clinical fellow of the Medical Research Council UK (G117/394).

³ Supported by a predoctoral fellowship from IWT-Vlaanderen.

⁵ Supported by a postdoctoral fellowship from IWT-Vlaanderen (OZM/030508).

⁴ To whom correspondence should be addressed: CMPG, Kasteelpark Arenberg 20, B-3001 Heverlee, Belgium. Tel.: 32-16-32-96-82; Fax: 32-16-32-19-66; E-mail: bruno.cammue{at}biw.kuleuven.be.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?