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Journal of Bacteriology, February 1999, p. 700-708, Vol. 181, No. 3
Institut de Recherches Cliniques de
Montréal, Montréal, Québec, Canada H2W 1R7
Received 18 August 1998/Accepted 28 October 1998
Candida albicans is an opportunistic pathogenic yeast
which frequently develops resistance to the antifungal agent
fluconazole (FCZ) in patients undergoing long-term therapy.
FCZ-resistant strains often display a reduced intracellular FCZ
accumulation which correlates with the overexpression of the
ATP-binding cassette transporters CDR1 and CDR2
or the major facilitator (MF) MDR1. We have recently cloned
a C. albicans gene, named CAP1, which codes for
a bZip transcription factor of the AP-1 family homologous to the Yap1
protein involved in multidrug resistance and response to oxidative
stress in Saccharomyces cerevisiae. CAP1 was found to
confer FCZ resistance in S. cerevisiae by transcriptionally activating FLR1, a gene coding for an MF homologous to the
C. albicans MDR1 gene product (A.-M. Alarco, I. Balan, D. Talibi, N. Mainville, and M. Raymond, J. Biol. Chem.
272:19304-19313, 1997). To study the role of CAP1 in
C. albicans, we constructed a CAI4-derived mutant strain
carrying a homozygous deletion of the CAP1 gene (CJD21). We
found that deletion of CAP1 did not affect the
susceptibility of CJD21 cells to FCZ, cerulenin, brefeldin A, and
diamide but caused hypersensitivity to cadmium, 4-nitroquinoline N-oxide, 1,10-phenanthroline, and hydrogen peroxide, an
effect which was reverted by reintroduction of the CAP1
gene in these cells. Introduction of a hyperactive truncated allele of
CAP1 (CAP1-TR) in CJD21 resulted in resistance
of the cells to all of the above compounds except hydrogen peroxide.
The hyperresistant phenotype displayed by the CJD21 CAP1-TR
transformants was found to correlate with the overexpression of a
number of potential CAP1 transcriptional targets such as
MDR1, CaYCF1, CaGLR1, and CaTRR1. Taken together, our results demonstrate that
CAP1 is involved in multidrug resistance and oxidative
stress response in C. albicans. Finally, disruption of
CAP1 in strain FR2, selected in vitro for FCZ resistance
and constitutively overexpressing MDR1, did not suppress
but rather increased the levels of MDR1 expression,
demonstrating that CAP1 acts as a negative transcriptional
regulator of the MDR1 gene in FR2 and is not responsible
for MDR1 overexpression in this strain.
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
The bZip Transcription Factor Cap1p Is Involved in
Multidrug Resistance and Oxidative Stress Response in
Candida albicans
*
Corresponding author. Mailing address: Institut de
Recherches Cliniques de Montréal, 110 Pine Ave., West,
Montréal, Québec, Canada H2W 1R7. Phone: (514) 987-5770. Fax: (514) 987-5732. E-mail: raymonm{at}ircm.qc.ca.
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