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Antimicrobial Agents and Chemotherapy, February 2004, p. 561-567, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.561-567.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Differential Gene Expression in Auristatin PHE-Treated Cryptococcus neoformans

Tanja Woyke,1,2 Michael E. Berens,3 Dominique B. Hoelzinger,3 George R. Pettit,1,4 Günther Winkelmann,2 and Robin K. Pettit1,5*

Cancer Research InstituteDepartments of,1 Microbiology,5 Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287,4 Eberhard Karls University Tübingen, 72076 Tübingen, Germany,2 Translational Genomics Research Institute, Phoenix, Arizona 850043

Received 18 June 2003/ Returned for modification 30 July 2003/ Accepted 24 October 2003

The antifungal pentapeptide auristatin PHE was recently shown to interfere with microtubule dynamics and nuclear and cellular division in the opportunistic pathogen Cryptococcus neoformans. To gain a broader understanding of the cellular response of C. neoformans to auristatin PHE, mRNA differential display (DD) and reverse transcriptase PCR (RT-PCR) were applied. Examination of approximately 60% of the cell transcriptome from cells treated with 1.5 times the MIC (7.89 µM) of auristatin PHE for 90 min revealed 29 transcript expression differences between control and drug-treated populations. Differential expression of seven of the transcripts was confirmed by RT-PCR, as was drug-dependent modulation of an additional seven transcripts by RT-PCR only. Among genes found to be differentially expressed were those encoding proteins involved in transport, cell cycle regulation, signal transduction, cell stress, DNA repair, nucleotide metabolism, and capsule production. For example, RHO1 and an open reading frame (ORF) encoding a protein with 91% similarity to the Schizophyllum commune 14-3-3 protein, both involved in cell cycle regulation, were down-regulated, as was the gene encoding the multidrug efflux pump Afr1p. An ORF encoding a protein with 57% identity to the heat shock protein HSP104 in Pleurotus sajor-caju was up-regulated. Also, three transcripts of unknown function were responsive to auristatin PHE, which may eventually contribute to the elucidation of the function of their gene products. Further study of these differentially expressed genes and expression of their corresponding proteins are warranted to evaluate how they may be involved in the mechanism of action of auristatin PHE. This information may also contribute to an explanation of the selectivity of auristatin PHE for C. neoformans. This is the first report of drug action using DD in C. neoformans.

* Corresponding author. Mailing address: Cancer Research Institute, Arizona State University, Tempe, AZ 85287-2404. Phone: (480) 965-4907. Fax: (480) 965-8558. E-mail: pettitr{at}asu.edu.

Antimicrobial Agents and Chemotherapy, February 2004, p. 561-567, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.561-567.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rodrigues, M. L., Nakayasu, E. S., Oliveira, D. L., Nimrichter, L., Nosanchuk, J. D., Almeida, I. C., Casadevall, A. (2008). Extracellular Vesicles Produced by Cryptococcus neoformans Contain Protein Components Associated with Virulence. Eukaryot Cell 7: 58-67 [Abstract] [Full Text]  


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