期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 404, 期 2, 页码 183-201出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2010.09.016
关键词
amino acid control response; oxidative stress; Int6/eIF3e; Gcn2; MAP kinase
资金
- Kansas IDeA Network of Biomedical Research Excellence, National Institutes of Health Center for Research Resources [P20 RR016475]
- Kansas State University Terry Johnson Cancer Center
- National Institutes of Health [GM67481, GM49164]
- Cancer Research UK [12485] Funding Source: researchfish
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, int6 Delta 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 gcn2 Delta 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. (C) 2010 Elsevier Ltd. All rights reserved.
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