Academic journal article Genetics

The Hog1 Mitogen-Activated Protein Kinase Mediates a Hypoxic Response in Saccharomyces Cerevisiae

Academic journal article Genetics

The Hog1 Mitogen-Activated Protein Kinase Mediates a Hypoxic Response in Saccharomyces Cerevisiae

Article excerpt

ABSTRACT

We have studied hypoxic induction of transcription by studying the seripauperin (PAU) genes of Saccharomyces cerevisiae. Previous studies showed that PAU induction requires the depletion of heme and is dependent upon the transcription factor Upc2. We have now identified additional factors required for PAU induction during hypoxia, including Hog1, a mitogen-activated protein kinase (MAPK) whose signaling pathway originates at the membrane. Our results have led to a model in which heme and ergosterol depletion alters membrane fluidity, thereby activating Hog1 for hypoxic induction. Hypoxic activation of Hog1 is distinct from its previously characterized response to osmotic stress, as the two conditions cause different transcriptional consequences. Furthermore, Hog1-dependent hypoxic activation is independent of the S. cerevisiae general stress response. In addition to Hog1, specific components of the SAGA coactivator complex, including Spt20 and Sgf73, are also required for PAU induction. Interestingly, the mammalian ortholog of Spt20, p38IP, has been previously shown to interact with the mammalian ortholog of Hog1, p38. Taken together, our results have uncovered a previously unknown hypoxic-response pathway that may be conserved throughout eukaryotes.

CHANGES in the environmental level of molecular oxygen can have profound effects on the growth of most organisms. Oxygen is required as an electron receptor in aerobic respiration, as well as for the biosynthesis of sterols, unsaturated fatty acids (UFAs), and heme, all of which are essential cellular components (Rosenfeld and Beauvoit 2003). In contrast, oxygen can also have negative consequences when it is metabolized into reactive oxygen species that can damage cellular components ( Jamieson 1998). To adapt to altered levels of oxygen in the environment, most organisms, from bacteria to humans, respond to changes in oxygen levels by extensive changes in transcription (Bunn and Poyton 1996).

Several distinct mechanisms govern how cells respond to low levels of oxygen (hypoxia) in both metazoans and microorganisms, and four have been well described. First, in metazoans, many genes are induced during hypoxia by the transcription factor, hypoxia-inducible factor (HIF) (Kaelin 2005). In the presence of oxygen, HIF is inhibited by an oxygen-dependent hydroxylation that targets HIF for degradation; however, when oxygen levels are low, this hydroxylation cannot occur and HIF accumulates to activate transcription. Second, in Rhizobia and other bacterial species, the FixJ transcription factor promotes transcription during hypoxia (Rodgers 1999; Delgado-Nixon et al. 2000). Oxygen, when present, binds to a heme molecule attached to FixL, a histidine kinase, thereby preventing it from phosphorylating and activating FixJ. Third, in the yeast Schizosaccharomyces pombe, the transcription factor, sterol regulatory elementbinding protein (SREBP) is activated during hypoxia (Hughes et al. 2005). This activation is caused by a decreased level of sterols, whose biosynthesis is oxygen dependent. Like its human ortholog, SREBP is tethered to a cellular membrane and is released to the nucleus when sterol levels are low (Brown and Goldstein 1997; Delgado-Nixon et al. 2000). While there is no SREBP ortholog in Saccharomyces cerevisiae, the Upc2 transcription factor is considered a functional homolog (Vik and Rine 2001) and is one focus of this work. Finally, S. cerevisiae contains an oxygen-responsive transcription factor, Hap1, that is described below.

In S. cerevisiae, ~400 genes respond to changes in oxygen levels. Several studies have shown that Hap1 plays a prominent role in this regulation, under both hypoxic and aerobic conditions (Zitomer and Lowry 1992; Ter Linde et al. 1999; Becerra et al. 2002; Kwast et al. 2002; Lai et al. 2005, 2006; Hickman and Winston 2007). Hap1 directly regulates many aerobic genes through activation in the presence of oxygen and repression in hypoxia (Zitomer and Lowry 1992; Hickman and Winston 2007). …

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