title: The roles of stress-activated Sty1 and Gcn2 kinases and of the protooncoprotein homologue Int6/eIF3e in responses to endogenous oxidative stress during histidine starvation.
abstract: In fission yeast, Sty1 and Gcn2 are important protein kinases that regulate gene expression in response to amino acid starvation. The translation factor subunit Int6/eIF3e promotes Sty1-dependent response by increasing the abundance of Atf1, a transcription factor targeted by Sty1. While Gcn2 promotes expression of amino acid biosynthesis enzymes, the mechanism and function of Sty1 activation and Int6/eIF3e involvement during this nutrient stress are not understood. Here we show that mutants lacking sty1(+) or gcn2(+) display reduced viabilities during histidine depletion stress in a manner suppressible by the antioxidant N-acetyl cysteine, suggesting that these protein kinases function to alleviate endogenous oxidative damage generated during nutrient starvation. Int6/eIF3e also promotes cell viability by a mechanism involving the stimulation of Sty1 response to oxidative damage. In further support of these observations, microarray data suggest that, during histidine starvation, int6Δ increases the duration of Sty1-activated gene expression linked to oxidative stress due to the initial attenuation of Sty1-dependent transcription. Moreover, loss of gcn2 induces the expression of a new set of genes not activated in wild-type cells starved for histidine. These genes encode heatshock proteins, redox enzymes, and proteins involved in mitochondrial maintenance, in agreement with the idea that oxidative stress is imposed on gcn2Δ cells. Furthermore, early Sty1 activation promotes rapid Gcn2 activation on histidine starvation. These results suggest that Gcn2, Sty1, and Int6/eIF3e are functionally integrated and cooperate to respond to oxidative stress generated during histidine starvation.
authors.affiliation: Molecular, Cellular, and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nemoto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Udagawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohira
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Kouji
authors.initials: K
authors.lastname: Hirota
authors.forename: Caroline R M
authors.initials: CR
authors.lastname: Wilkinson
authors.forename: Jürg
authors.initials: J
authors.lastname: Bähler
authors.forename: Nic
authors.initials: N
authors.lastname: Jones
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ohta
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.forename: Katsura
authors.initials: K
authors.lastname: Asano
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D000640:Amitrole / Q000494:pharmacology; D001483:Base Sequence; D004271:DNA, Fungal / Q000235:genetics; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D006639:Histidine / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051697:Activating Transcription Factor 1; D004271:DNA, Fungal; D039621:Eukaryotic Initiation Factor-3; D010750:Phosphoproteins; D029702:Schizosaccharomyces pombe Proteins; C106740:atf1 protein, S pombe; D006639:Histidine; C539007:Gcn2 protein, S pombe; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe; D000640:Amitrole