Pkc1 and the Upstream Elements of the Cell Integrity Pathway in Saccharomyces cerevisiae, Rom2 and Mtl1, Are Required for Cellular Responses to Oxidative Stress

Vilella, Felipe; Herrero, Enrique; Torres, Jordi; Torre-Ruiz, María Ángeles de la

doi:10.1074/jbc.m411062200

Cited by 132 publications

(180 citation statements)

References 46 publications

(47 reference statements)

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“…Nevertheless, contrary to S. cerevisiae Slt2p (Vilella et al, 2005), diamide activates Mkc1p even in a pkc1D mutant, and mkc1D mutants are more sensitive to this agent. Diamide could directly affect either Mkc1p or elements of the cell integrity pathway other than Pkc1p.…”

Section: Discussionmentioning

confidence: 99%

The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans

et al. 2005

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Candida albicans is an opportunistic pathogen that has adapted to live and grow in the human body as its natural environment. Under these conditions, this fungus faces numerous challenges, including oxidative, osmotic and enzymic processes that may damage external and internal structures. In view of the key role of MAP kinase signalling pathways in the physiology of C. albicans, the effect of agents mimicking in vivo environmental conditions on the activation of the p42-44 MAP kinases has been analysed. It has been found that Mkc1p is phosphorylated in the presence of oxidative stress, changes in osmotic pressure, cell wall damage and a decrease in the growth temperature. This phosphorylation is dependent on Pkc1p, indicating that both proteins operate in the same signalling pathway in C. albicans. Under some stimuli, the phosphorylation of Mkc1p required the presence of Hog1p, the MAP kinase of the high osmolarity glycerol (HOG) pathway. This suggests the existence of a new regulatory role, at least under some conditions, for these MAP kinase pathways in yeast.

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Section: Discussionmentioning

confidence: 99%

The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans

et al. 2005

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Section: Introductionmentioning

confidence: 99%

“…S. cerevisiae is also able to sense the opposite situation -hypoosmotic conditions -through the cell-integrity pathway mediated by the Slt2 MAP kinase, which is activated in response to high temperatures, low osmolarity and cell-wall degrading compounds (Davenport et al, 1995;Kamada et al, 1995; Martín et al, 2000). Recently, activation of the Slt2 MAP kinase by oxidizing agents (hydrogen peroxide and diamide) has been reported (Vilella et al, 2005).In fission yeast, a functional-homologue route to the HOG pathway is mediated by the Sty1 MAP kinase, which responds to several stresses, such as heat and cold shock and osmotic and oxidative stress (Samejima et al, 1997; Shiozaki Russell, 1996;Soto et al, 2002). sty1 2 mutants are sterile and exhibit a G 2 cell-cycle delay, indicating additional roles for Sty1 in meiosis and cell-cycle progression (Millar, 1999;Shiozaki & Russell, 1995.…”

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The Pbs2 MAP kinase kinase is essential for the oxidative-stress response in the fungal pathogen Candida albicans

et al. 2005

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The human fungal pathogen Candida albicans responds to stress by phosphorylation of the Hog1 MAP kinase. PBS2 was cloned and shown to encode the MAP kinase kinase that is involved in this activation, as determined by immunoblot analyses using antibodies that recognize the active form of the target Hog1 protein. Characterization of pbs2 mutants revealed that they were sensitive to both osmotic and oxidative stress and that they, interestingly, displayed differential behaviour from that of hog1 mutants, losing viability when exposed to an oxidative challenge more rapidly than the hog1 strain. Hog1 and Pbs2 were also shown to be involved in the mechanism of adaptation to oxidative stress, as evidenced by the enhanced susceptibility to oxidants of pbs2 and hog1 mutants, compared with the wild-type strain, when cells were previously exposed to a low, sub-lethal concentration of hydrogen peroxide and by the PBS2-dependent diminished activation of Hog1 MAP kinase in the adaptive process. Studies with a chimaeric Hog1-green fluorescent protein fusion revealed that this protein was localized throughout the cell (being excluded from the vacuole), but concentrated in the nucleus in response to NaCl stress, a process that was dependent on the Pbs2 protein. Both Hog1 and Pbs2 also play a role in controlling the phosphorylation state of the other MAP kinases Mkc1 and Cek1, involved respectively in cell-wall integrity and invasive growth. Furthermore, it is demonstrated that PBS2 plays a role in cell-wall biogenesis in this fungal pathogen, as its deletion renders cells with an altered susceptibility to certain cell wall-interfering compounds. INTRODUCTIONEukaryotic cells respond to environmental changes through signal-transduction pathways. MAPK (mitogen-activated protein kinase) routes consist of a three-kinase module: the MAP kinase kinase kinase, the MAP kinase kinase and the MAP kinase, which are activated by sequential phosphorylation in response to different extracellular signals. These pathways are conserved through evolution (Kültz & Burg, 1998) and their functionality is well-documented in some model organisms, such as Saccharomyces cerevisiae and Schizosaccharomyces pombe (Banuett, 1998;Gustin et al., 1998). In budding yeast, six MAPK pathways have been described that perform essential functions in fungal physiology, such as mating, pseudohyphal/invasive growth, cellwall integrity, STE vegetative growth (SVG), spore-wall assembly and adaptation to high osmolarity (HOG) (Gustin et al., 1998;Posas et al., 1998). This last route is activated in response to osmotic and -as described recently -oxidative stress (Haghnazari & Heyer, 2004;Singh, 2000) and mutant cells in some elements of the pathway are sensitive to both kinds of stresses. Osmosensitivity is partially explained by the inability to increase intracellular glycerol under restrictive conditions in order to counteract the extracellular turgor (Albertyn et al., 1994). Under hyperosmotic conditions, hog1 and pbs2 mutant strains display different alterations, suc...

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“…In budding yeast the MAPK 3 pathways are not well characterized for sensing and transmitting oxidative stress to the cytoplasm and nuclear elements. However, Mtl1 has already been characterized as a receptor for oxidative stress (1). Mtl1 was initially identified as a yeast homologue of Mid2 by Rajavel et al (2) who observed that it performed a function in cell integrity signaling involved in vegetative growth.…”

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Mtl1 Is Required to Activate General Stress Response through Tor1 and Ras2 Inhibition under Conditions of Glucose Starvation and Oxidative Stress

Petkova

Pujol-Carrion

Arroyo

et al. 2010

Journal of Biological Chemistry

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Mtl1 is a member of the cell wall integrity (CWI) pathway of Saccharomyces cerevisiae, which functions as a cell wall sensor for oxidative stress. Genome-wide transcriptional analysis revealed a cluster of genes that were down-regulated in the absence of Mtl1. Many of these genes were potentially regulated by the general stress response factor Msn2/Msn4. In response to rapamycin, caffeine, glucose starvation and oxidative stress provoked by H 2 O 2 , mtl1 presents a significant loss of viability as well as a deficiency in the transcriptional response mediated by Msn2/Msn4. The Mtl1 function was required (i) to induce ribosomal gene repression, (ii) to induce the general stress response driven by the transcription factor Msn2/Msn4, and (iii) to activate the CWI pathway in response to both glucose starvation and oxidative stress. We also detected higher cAMP levels in the mtl1 mutant than in wild type cells indicative of up-regulated RAS2-PKA activity. Disruption of TOR1, disruption of RAS2, or hyperactivation of Rho1 restored both the viability and the transcriptional function (both ribosomal and Msn2/Msn4-dependent gene expression) in the mtl1 mutant to almost wild type levels when cells were starved of glucose or stressed with H 2 O 2 . Taking our results together, we propose an essential role for Mtl1 in signaling oxidative stress and quiescence to the CWI pathway and to the general stress response through Rho1 and the inhibition of either the TOR1 or RAS2 functions. These mechanisms would be required to allow cells to adapt to both oxidative and nutritional stresses.

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Pkc1 and the Upstream Elements of the Cell Integrity Pathway in Saccharomyces cerevisiae, Rom2 and Mtl1, Are Required for Cellular Responses to Oxidative Stress

Cited by 132 publications

References 46 publications

The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans

The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans

The Pbs2 MAP kinase kinase is essential for the oxidative-stress response in the fungal pathogen Candida albicans

Mtl1 Is Required to Activate General Stress Response through Tor1 and Ras2 Inhibition under Conditions of Glucose Starvation and Oxidative Stress

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