Open AccessComparative Transcriptome Analysis Reveals Novel Roles of the Ras and Cyclic AMP Signaling Pathways in Environmental Stress Response and Antifungal Drug Sensitivity in Cryptococcus neoformans
Author(s) -
Shinae Maeng,
Young-Joon Ko,
Gyu Bum Kim,
Kwang Woo Jung,
Anna Floyd,
Joseph Heitman,
Yong-Sun Bahn
Publication year - 2010
Publication title -
eukaryotic cell
Language(s) - English
Resource type - Journals
eISSN - 1535-9778
pISSN - 1535-9786
DOI - 10.1128/ec.00309-09
Subject(s) - cryptococcus neoformans , transcriptome , biology , antifungal drug , mutant , adenylyl cyclase , signal transduction , fungal protein , heat shock , gene , microbiology and biotechnology , microarray analysis techniques , genetics , heat shock protein , gene expression , candida albicans
The cyclic AMP (cAMP) pathway plays a central role in the growth, differentiation, and virulence of pathogenic fungi, includingCryptococcus neoformans . Three upstream signaling regulators of adenylyl cyclase (Cac1), Ras, Aca1, and Gpa1, have been demonstrated to control the cAMP pathway inC. neoformans , but their functional relationship remains elusive. We performed a genome-wide transcriptome analysis with a DNA microarray using theras1 Δ,gpa1 Δ,cac1 Δ,aca1 Δ, andpka1 Δpka2 Δ mutants. Theaca1 Δ,gpa1 Δ,cac1 Δ, andpka1 Δpka2 Δ mutants displayed similar transcriptome patterns, whereas theras1 Δ mutant exhibited transcriptome patterns distinct from those of the wild type and the cAMP mutants. Interestingly, a number of environmental stress response genes are modulated differentially in theras1 Δ and cAMP mutants. In fact, the Ras signaling pathway was found to be involved in osmotic and genotoxic stress responses and the maintenance of cell wall integrity via the Cdc24-dependent signaling pathway. Notably, the Ras and cAMP mutants exhibited hypersensitivity to a polyene drug, amphotericin B, without showing effects on ergosterol biosynthesis, which suggested a novel method of antifungal combination therapy. Among the cAMP-dependent gene products that we characterized, two small heat shock proteins, Hsp12 and Hsp122, were found to be involved in the polyene antifungal drug susceptibility ofC. neoformans .