Mitogen-activated protein kinase stimulation of Ca(2+) signaling is required for survival of endoplasmic reticulum stress in yeast.
Endoplasmic reticulum (ER) stress in the budding yeast Saccharomyces cerevisiae triggers Ca2+ influx through a plasma membrane channel composed of Cch1 and Mid1. This response activates calcineurin, which helps to prevent cell death during multiple forms of ER stress, including the response to azole-class antifungal drugs. Herein, we show that ER stress activates the cell integrity mitogen-activate protein kinase cascade in yeast and that the activation of Pkc1 and Mpk1 is necessary for stimulation of the Cch1-Mid1 Ca2+ channel independent of many known targets of Mpk1 (Rlm1, Swi4, Swi6, Mih1, Hsl1, and Swe1). ER stress generated in response to miconazole, tunicamycin, or other inhibitors also triggered a transient G2/M arrest that depended upon the Swe1 protein kinase. Calcineurin played little role in the Swe1-dependent cell cycle arrest and Swe1 had little effect on calcineurin-dependent avoidance of cell death. These findings help to clarify the interactions between Mpk1, calcineurin, and Swe1 and suggest that the calcium cell survival pathway promotes drug resistance independent of both the unfolded protein response and the G2/M cell cycle checkpoint.
D000935:Antifungal Agents / Q000633:toxicity; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D018797:Cell Cycle Proteins; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism; D016195:G2 Phase / Q000502:physiology; D026161:MADS Domain Proteins; D008562:Membrane Glycoproteins / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases; D008938:Mitosis / Q000502:physiology; D017510:Protein Folding; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D020666:ras-GRF1
D000935:Antifungal Agents; C108765:CCH1 protein, S cerevisiae; C542351:CDC25 protein, S cerevisiae; D015220:Calcium Channels; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D026161:MADS Domain Proteins; C090463:MID1 protein, S cerevisiae; D008562:Membrane Glycoproteins; C095725:RLM1 protein, S cerevisiae; C062214:SWI4 protein, S cerevisiae; C075111:SWI6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D020666:ras-GRF1; D011494:Protein Kinases; C097993:Pkc1 protein, Trichoderma reesei; C099685:SWE1 protein, S cerevisiae; D011505:Protein-Tyrosine Kinases; C106494:HSL1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae; D019703:Calcineurin; D017027:Protein Tyrosine Phosphatases; D002118:Calcium