Comparative transcriptome analysis reveals novel roles of the ras and cyclic AMP signaling pathways in environmental stress response and antifungal drug sensitivity in Cryptococcus neoformans

Shinae Maeng, Young Joon Ko, Gyu Bum Kim, Kwang Woo Jung, Anna Floyd, Joseph Heitman, Yong Sun Bahn

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

The cyclic AMP (cAMP) pathway plays a central role in the growth, differentiation, and virulence of pathogenic fungi, including Cryptococcus neoformans. Three upstream signaling regulators of adenylyl cyclase (Cac1), Ras, Aca1, and Gpa1, have been demonstrated to control the cAMP pathway in C. neoformans, but their functional relationship remains elusive. We performed a genome-wide transcriptome analysis with a DNA microarray using the ras1δ, gpa1δ, cac1δ, aca1δ, and pka1δ pka2δ mutants. The aca1δ, gpa1δ, cac1δ, and pka1δ pka2δ mutants displayed similar transcriptome patterns, whereas the ras1δ 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 the ras1δ 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 of C. neoformans.

Original languageEnglish
Pages (from-to)360-378
Number of pages19
JournalEukaryotic Cell
Volume9
Issue number3
DOIs
Publication statusPublished - 2010 Mar 1

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Cryptococcus neoformans
Gene Expression Profiling
Cyclic AMP
Pharmaceutical Preparations
Polyenes
Transcriptome
Small Heat-Shock Proteins
Osmoregulation
Ergosterol
Amphotericin B
Oligonucleotide Array Sequence Analysis
Adenylyl Cyclases
Cell Wall
Genes
DNA Damage
Virulence
Hypersensitivity
Fungi
Maintenance
Genome

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Cite this

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abstract = "The cyclic AMP (cAMP) pathway plays a central role in the growth, differentiation, and virulence of pathogenic fungi, including Cryptococcus neoformans. Three upstream signaling regulators of adenylyl cyclase (Cac1), Ras, Aca1, and Gpa1, have been demonstrated to control the cAMP pathway in C. neoformans, but their functional relationship remains elusive. We performed a genome-wide transcriptome analysis with a DNA microarray using the ras1δ, gpa1δ, cac1δ, aca1δ, and pka1δ pka2δ mutants. The aca1δ, gpa1δ, cac1δ, and pka1δ pka2δ mutants displayed similar transcriptome patterns, whereas the ras1δ 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 the ras1δ 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 of C. neoformans.",
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Comparative transcriptome analysis reveals novel roles of the ras and cyclic AMP signaling pathways in environmental stress response and antifungal drug sensitivity in Cryptococcus neoformans. / Maeng, Shinae; Ko, Young Joon; Kim, Gyu Bum; Jung, Kwang Woo; Floyd, Anna; Heitman, Joseph; Bahn, Yong Sun.

In: Eukaryotic Cell, Vol. 9, No. 3, 01.03.2010, p. 360-378.

Research output: Contribution to journalArticle

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