The Flo8 transcription factor is essential for hyphal development and virulence in Candida albicans. Mol Biol Cell

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Molecular Biology of the Cell (Impact Factor: 4.55). 02/2006; 17(1):295-307. DOI: 10.1091/mbc.E05-06-0502
Source: PubMed

ABSTRACT The transcription factor Flo8 is essential for filamentous growth in Saccharomyces cerevisiae and is regulated under the cAMP/protein kinase A (PKA) pathway. To determine whether a similar pathway/regulation exists in Candida albicans, we have cloned C. albicans FLO8 by its ability to complement S. cerevisiae flo8. Deleting FLO8 in C. albicans blocked hyphal development and hypha-specific gene expression. The flo8/flo8 mutant is avirulent in a mouse model of systemic infection. Genome-wide transcription profiling of efg1/efg1 and flo8/flo8 using a C. albicans DNA microarray suggests that Flo8 controls subsets of Efg1-regulated genes. Most of these genes are hypha specific, including HGC1 and IHD1. We also show that Flo8 interacts with Efg1 in yeast and hyphal cells by in vivo immunoprecipitation. Similar to efg1/efg1, flo8/flo8 and cdc35/cdc35 show enhanced hyphal growth under an embedded growth condition. Our results suggest that Flo8 may function downstream of the cAMP/PKA pathway, and together with Efg1, regulates the expression of hypha-specific genes and genes that are important for the virulence of C. albicans.

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    • "Cells lacking any of these repressors constitutively grow as long pseudohyphae, as the expression of hyphal-specific genes is not inhibited (Kadosh and Johnson, 2005; Murad et al., 2001; Sudbery, 2011). The up-regulation of the expression of hyphal-specific genes is accomplished by several transcription factors, including Efg1, Chp1, Cph2, Tec1, Flo8, Czf1, Rim101 and Ndt80 (Shapiro et al., 2011; Sudbery, 2011; Stoldt et al., 1997; Lane et al., 2001; Cao et al., 2006; Davis et al., 2000; Sellam et al., 2010). Efg1 is necessary for the formation of hyphae in response to serum, neutral pH, CO 2 and GlcNAc in liquid media and on solid spider media. "
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    ABSTRACT: Candida albicans is the most common fungal pathogen of humans, forming both commensal and opportunistic pathogenic interactions, causing a variety of skin and soft tissue infections in healthy people. In immunocompromised patients C. albicans can result in invasive, systemic infections that are associated with a high incidence of mortality. Propolis is a complex mixture of several resinous substances which are collected from plants by bees. Here, we demonstrated the fungicidal activity of propolis against all three morphogenetic types of C. albicans and that propolis-induced cell death was mediated via metacaspase and Ras signaling. To identify genes that were involved in propolis tolerance, we screened ∼ 800 C. albicans homozygous deletion mutants for decreased tolerance to propolis Fifty-one mutant strains were identified as being hypersensitive to propolis including seventeen genes involved in cell adhesion, biofilm formation, filamentous growth, phenotypic switching and pathogenesis (HST7, GIN4, VPS34, HOG1, ISW2, SUV3, MDS3, HDA2, KAR3, YHB1, NUP85, CDC10, MNN9, ACE2, FKH2, and SNF5). We validated these results by showing that propolis inhibited the transition from yeast-like to hyphal growth. Propolis was shown to contain compounds that conferred fluorescent properties to C. albicans cells. Moreover, we have shown that a topical pharmaceutical preparation, based upon propolis, was able to control C. albicans infections in a mouse model for vulvovaginal candidiasis. Our results strongly indicate that propolis could be a used as a strategy for controlling candidiasis.
    Fungal Genetics and Biology 07/2013; 60. DOI:10.1016/j.fgb.2013.07.001 · 3.26 Impact Factor
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    • "Consistent with the phenotype observed in the bcr1/ bcr1 cyr1/cyr1 double mutant, two major transcription regulators downstream of cAMP signalling, Efg1 and Flo8, are also required for hyper-filamentation of the bcr1/bcr1 mutant. Filamentous-specific G1 cyclin-related protein Hgc1 is transcriptionally regulated by the cAMP pathway and the Efg1 and Flo8 transcription regulators (Zheng and Wang, 2004; Cao et al., 2006). HGC1 is essential for opaque cell filamentation in the bcr1/bcr1 mutant (Fig. 8A). "
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    ABSTRACT: The human fungal pathogen Candida albicans has at least two types of morphological transitions: white to opaque cell transitions and yeast to hyphal transitions. Opaque cells have historically not been known to undergo filamentation under standard filament-inducing conditions. Here we find that Bcr1 and its downstream regulators Cup9, Nrg1 and Czf1 and the cAMP-signaling pathway control opaque cell filamentation in C. albicans. We have shown that deletion of BCR1, CUP9, NRG1 and CZF1 results in opaque cell filamentation under standard culture conditions. Disruption of BCR1 in white cells has no obvious effect on hyphal growth, suggesting that Bcr1 is an opaque-specific regulator of filamentation under the conditions tested. Moreover, inactivation of the cAMP-signaling pathway or disruption of its downstream transcriptional regulators, FLO8 and EFG1, strikingly attenuates filamentation in opaque cells of the bcr1/bcr1 mutant. Deletion of HGC1, a downstream gene of the cAMP-signaling pathway encoding G1 cyclin-related protein, completely blocks opaque cell filamentation induced by inactivation of BCR1. These results demonstrate that Bcr1 regulated opaque cell filamentation is dependent on the cAMP-signaling pathway. This study establishes a link between the white-opaque switch and the yeast-filamentous growth transition in C. albicans.
    Molecular Microbiology 06/2013; DOI:10.1111/mmi.12310 · 5.03 Impact Factor
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    • "Well-established DNA array technology allows efficient analysis of the genome-wide expression of multiple strains, mutants and different growth conditions. Much work has been published about issues such as the yeast-to-hypha transition (Nantel et al. 2002), cyclic AMP signalling (Harcus et al. 2004), the regulation of morphogenesis and metabolism by APSES proteins (Doedt et al. 2004), the role of the FLO8 transcription factor in hyphal development (Cao et al. 2006), the convergent regulation of virulence by Cph1p, Cph2p and Efg1p (Lane et al. 2001), the Tac1p regulon (Liu et al. 2007), the response to steroids (Banerjee et al. 2007), etc. Despite such a large body of information, we still lack the transcriptomes of C. albicans obtained under standard and well defined sets of conditions. "
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    ABSTRACT: One of the main parameters involved in the yeast-to- hypha transition in Candida albicans is temperature, and this change is involved in its pathogenicity. A complete switch betweenyeastandhyphacanbeachievedbychangingthe temperature from 28°C to 37°C in Lee medium supplemented with serum. To compare the early transcriptional response of C. albicans to temperature, we have carried out a genome- wide analysis of the C. albicans response to temperature after a 5-min exposure at 37°C. Using a cDNA microarray method, we found changes in 1,635 genes, suggesting that the key time for controlling the dimorphic change occurs very early. The overrepresented categories of up-regulated genes consisted of transporters, transcription factor and translation initiation factors, ribosomal proteins, DNA-directed RNA polymerase, cell cycle and cell polarity, RNA helicase and genes encoding polyamine biosynthesis. The main categories of down- regulated genes included: carbohydrate metabolism, actin filament organization, electron transport and ATP biosynthesis, respiration, histone assembly , and ergosterol biosynthesis. Collectively, these results demonstrate that much of the gene regulation observed is during the early stage of yeast-to-hypha transition.
    Comparative Clinical Pathology 12/2011; DOI 10.1007/s00580-011-1325-1. DOI:10.1007/s00580-011-1325-1
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