The regulation of the response of Candida albicans to hypoxic (low-oxygen) conditions is poorly understood. We used microarray and other transcriptional analyses to investigate the role of the Upc2 and Bcr1 transcription factors in controlling expression of genes involved in cell wall metabolism, ergosterol synthesis, and glycolysis during adaptation to hypoxia. Hypoxic induction of the ergosterol pathway is mimicked by treatment with sterol-lowering drugs (ketoconazole) and requires UPC2. Expression of three members of the family CFEM (common in several fungal extracellular membranes) of cell wall genes (RBT5, PGA7, and PGA10) is also induced by hypoxia and ketoconazole and requires both UPC2 and BCR1. Expression of glycolytic genes is induced by hypoxia but not by treatment with sterol-lowering drugs, whereas expression of respiratory pathway genes is repressed. However, Upc2 does not play a major role in regulating expression of genes required for central carbon metabolism. Our results indicate that regulation of gene expression in response to hypoxia in C. albicans is complex and is signaled both via lowered sterol levels and other unstudied mechanisms. We also show that induction of filamentation under hypoxic conditions requires the Ras1-and Cdc35-dependent pathway.The human fungal pathogen Candida albicans grows on superficial and internal sites in the infected host, areas that differ significantly in the availability of oxygen (26). Under low-oxygen (hypoxic) conditions, C. albicans switches from yeast to hyphal growth, a phenotypic change that has been associated with invasion and virulence (24,30,54). Exposure to hypoxia results in increased expression of genes involved in ergosterol synthesis and glycolysis and reduced expression of oxidative phosphorylation (3, 69). There is also an increase in expression of some cell wall and hyphal-specific genes (69), which is reflected in changes in the cell wall proteome (72).Although the response to hypoxia has been well studied in fungi such as Saccharomyces cerevisiae and Schizosaccharomyces pombe, much less is known about the response in C. albicans. In S. pombe, a decrease in oxygen is detected by the reduction in sterol synthesis, which requires 12 molecules of oxygen to convert one squalene to ergosterol (38). Sterol content is sensed by Sre1 and Scp1, which are homologs of the human sterol regulatory element binding protein (SREBP) and Scap (SREBP cleavage-activating protein) (38, 77). Sre1 and Scp1 are localized in the membrane, where they remain when sterol and oxygen levels are high. When sterol levels drop, the N terminus of Sre1 is cleaved off, and it enters the nucleus, where it acts as a transcriptional regulator. Sre1 is the major regulator of the hypoxic response in S. pombe and regulates expression of Ͼ100 genes (38). It also functions in a sterol-independent manner (39). SREBPs are also important for sensing oxygen levels in the pathogenic fungi Cryptococcus neoformans and Aspergillus fumigatus (7,13,85).There are no obvious SREBP orthologs in...