Isc1p Plays a Key Role in Hydrogen Peroxide Resistance and Chronological Lifespan through Modulation of Iron Levels and Apoptosis

Almeida, Teresa; Marques, M.; Mojžita, Dominik; Amorim, Maria Amélia; Silva, Rui D.; Almeida, Bruno; Rodrigues, Pedro; Ludovico, Paula; Hohmann, Stefan; Moradas‐Ferreira, Pedro; Côrte‐Real, Manuela; Costa, Vítor Santos

doi:10.1091/mbc.e07-06-0604

Cited by 91 publications

(115 citation statements)

References 66 publications

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“…2 Interestingly, ironinduced yeast death might involve Isc1p, a neutral sphingomyelinase that can be activated by cardiolipin and is involved in the biosynthesis of ceramide. 31 In fact, In addition, death of old cells within the colony center feeds the young cells at the colony margin (colony differentiation). The death of chronologically old cells preserves resources, releases nutrients, and allows adaptive regrowth (chronological aging), whereas replicatively old cells die for the good of young cells, which inherit the undamaged cellular material upon cellular division (replicative aging).…”

Section: Triggering Yeast Apoptosismentioning

confidence: 99%

Apoptosis in yeast: triggers, pathways, subroutines

et al. 2010

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A cell's decision to die is controlled by a sophisticated network whose deregulation contributes to the pathogenesis of multiple diseases including neoplastic and neurodegenerative disorders. The finding, more than a decade ago, that baker's yeast (Saccharomyces cerevisiae) can undergo apoptosis uncovered the possibility to investigate this mode of programmed cell death (PCD) in a model organism that combines both technical advantages and a eukaryotic 'cell room.' Since then, numerous exogenous and endogenous triggers have been found to induce yeast apoptosis and multiple yeast orthologs of crucial metazoan apoptotic regulators have been identified and characterized at the molecular level. Such apoptosis-relevant orthologs include proteases such as the yeast caspase as well as several mitochondrial and nuclear proteins that contribute to the execution of apoptosis in a caspase-independent manner. Additionally, physiological scenarios such as aging and failed mating have been discovered to trigger apoptosis in yeast, providing a teleological interpretation of PCD affecting a unicellular organism. Due to its methodological and logistic simplicity, yeast constitutes an ideal model organism that is efficiently helping to decipher the cell death regulatory network of higher organisms, including the switches between apoptotic, autophagic, and necrotic pathways of cellular catabolism. Here, we provide an overview of the current knowledge about the apoptotic subroutine of yeast PCD and its regulation.

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Section: Triggering Yeast Apoptosismentioning

confidence: 99%

Apoptosis in yeast: triggers, pathways, subroutines

et al. 2010

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“…Ceramide is a known bioactive lipid and has been shown to play an important role in cell processes such as growth, death, senescence, and response to stress (2,3). ISC1-deficient budding yeast exhibits a slower growth rate than wild type (WT) 2 strains (4) and higher sensitivity to high salt (NaCl) and hydrogen peroxide (5,6). A genome-wide screen revealed that ISC1 deletion (isc1⌬) mutants were sensitive to the DNA alkylating agent methyl methanesulfonate (MMS) and to the DNA replication blocking drug hydroxyurea (HU) (7).…”

mentioning

confidence: 99%

Hydroxyurea Sensitivity Reveals a Role for ISC1 in the Regulation of G2/M

Matmati

Kitagaki

Montefusco

et al. 2009

Journal of Biological Chemistry

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Saccharomyces cerevisiae cells lacking ISC1 (inositol phosphosphingolipase C) exhibit sensitivity to genotoxic agents such as methyl methanesulfonate and hydroxyurea (HU). Cell cycle analysis by flow cytometry revealed a G 2 /M block in isc1⌬ cells when treated with methyl methanesulfonate or HU. Further investigation revealed that the levels of Cdc28 phosphorylated on Tyr-19, which plays an essential role in the regulation of the G 2 /M checkpoint, were higher in synchronized and asynchronous cells lacking ISC1 in response to HU. Use of a Cdc28-Y19F mutant protected isc1⌬ from the G 2 /M block. In wild type cells, HU induced a loss of the Swe1p kinase, the enzyme that phosphorylates Cdc28-Tyr-19, correlating with resumption of the cell cycle. In the isc1⌬ cells, however, the levels of Swe1p remained at sustained high levels in response to HU. Significantly, deletion of SWE1 in an isc1⌬ background overcame the G 2 /M block in response to HU. The double isc1⌬/swe1⌬ mutant also overcame the growth defect on HU. Taken together, these findings implicate Isc1p as an upstream regulator of Swe1p levels and stability and Cdc28-Tyr-19 phosphorylation, in effect signaling recovery from the effects of genotoxic stress and allowing G 2 /M progression.In Saccharomyces cerevisiae, ISC1 (inositol phosphosphingolipase C) is the homologue of the mammalian neutral sphingomyelinase (nSMase 2). These enzymes catalyze the degradation of complex phospho-sphingolipids to produce phytoceramide/ dihydroceramide in yeast and ceramide/dihydroceramide in mammals (1). Ceramide is a known bioactive lipid and has been shown to play an important role in cell processes such as growth, death, senescence, and response to stress (2, 3). ISC1-deficient budding yeast exhibits a slower growth rate than wild type (WT) 2 strains (4) and higher sensitivity to high salt (NaCl) and hydrogen peroxide (5, 6). A genome-wide screen revealed that ISC1 deletion (isc1⌬) mutants were sensitive to the DNA alkylating agent methyl methanesulfonate (MMS) and to the DNA replication blocking drug hydroxyurea (HU) (7). However, the role of ISC1 in protecting cells from MMS or HU and its mechanism have not been investigated.MMS is a carcinogen that methylates DNA on N 7 -and N 3 -deoxyguanine (8 -10). HU is a ribonucleotide reductase inhibitor that blocks the synthesis of DNA. Yeast cells treated with HU activate the S phase checkpoint, and cells arrest in early S phase (11,12). After a few hours in the presence of HU, WT cells resume cell division, overcoming the S phase block.In this study, we investigate the mechanism and role of ISC1 in the response to HU. Cell cycle analysis using flow cytometry showed unexpectedly that deletion of ISC1 resulted in an additional and subsequent block in the G 2 /M phase in the presence of MMS or HU. The G 2 phase progression into M phase is regulated by the cyclin-dependent kinase Cdc28p (Cdk2 in mammals). Cdc28p is an essential regulator of the cell cycle in the yeast S. cerevisiae (13,14), and its activity is dependent on the bindi...

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“…A very recent work found that Isc1p played a key role in oxidative stress resistance and chronological lifespan (23). The study showed that Isc1p regulated cellular redox homeostasis through modulation of iron levels.…”

Section: The Yeast Nsmase: Isc1mentioning

confidence: 95%

Thematic Review Series: Sphingolipids. ISC1 (inositol phosphosphingolipid-phospholipase C), the yeast homologue of neutral sphingomyelinases

Matmati

Hannun

2008

Journal of Lipid Research

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Sphingolipid biosynthesis and breakdown in yeast share many homologies in their pathways with higher eukaryotes (Dickson, R. C. 1998. Sphingolipid functions in Saccharomyces cerevisiae: comparison to mammals. Annu. . In mammals, ceramide can be generated through hydrolysis of sphingomyelin catalyzed by sphingomyelinase (SMase). To date, as many as five SMases have been identified molecularly, separated into three main groups: acid, alkaline, and neutral SMases (nSMases) (Marchesini, N., and Y. Hannun. 2004. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem. Cell Biol. 82: 27-44). nSMase in mammals is represented by its homolog, inositol phosphosphingolipase C, codified by ISC1 in Saccharomyces cerevisiae (Sc) and Cryptococcus neoformans (Cn) and by CSS1 (Can't Stop Synthesizing cell wall) in Schizosaccharomyces pombe (Sp). Yeasts do not have sphingomyelin but instead have inositol phosphosphingolipids, which may function as orthologs of mammalian sphingomyelin. In this review, we will describe findings related to the function of ISC1, its localization, mechanisms, and its roles in cell response to different types of stresses. These studies serve as a foundation for the elucidation of the properties and functions of the extended family of nSMases. Ceramide has emerged as a highly studied bioactive and second-messenger lipid, with proposed roles in regulation of cell growth, cell death, senescence, and various stress responses (1, 2).A large number of enzymes are involved in regulating the levels of ceramide. To identify crucial enzymes that participate in the biochemical pathways leading to ceramide accumulation, many laboratories have focused on dissecting the biochemical pathways, and these studies have shown that ceramide can be produced in at least two distinct ways: the first is through the de novo pathway, which commences by the condensation of L-serine and palmitoyl-CoA, and the second by hydrolysis of complex lipids, especially sphingomyelin (3). The budding yeast, Saccharomyces cerevisiae (Sc), a fast-growing and genetically modifiable eukaryote, has been used extensively in elucidation of biochemical pathways of sphingolipid metabolism and functions of bioactive sphingolipids. In this review, we summarize findings about the enzyme that catalyzes the hydrolysis of yeast complex lipids to produce ceramide, ISC1 in Sc. We will also review other homologs of ISC1 in Schizosaccharomyces pombe (Sp), and the pathogen Cryptococcus neoformans (Cn), and then discuss implications for mammalian studies.Yeast and mammals share many similarities in sphingolipid metabolism (4), and these include the first two steps in the de novo pathway: synthesis of 3-ketodihydrosphingosine catalyzed by Lcb1p and Lcb2p in yeast, and by Sptlc1p and Sptlc2p in mammals. Lcb1p and Sptlc1p share 33% homology in their sequence, whereas Lcb2p and Sptlc2p have 48% sequence homology. These enzymes were first identified in yeast and later in mouse and human. The second step, characterized by the formation...

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Isc1p Plays a Key Role in Hydrogen Peroxide Resistance and Chronological Lifespan through Modulation of Iron Levels and Apoptosis

Cited by 91 publications

References 66 publications

Apoptosis in yeast: triggers, pathways, subroutines

Apoptosis in yeast: triggers, pathways, subroutines

Hydroxyurea Sensitivity Reveals a Role for ISC1 in the Regulation of G2/M

Thematic Review Series: Sphingolipids. ISC1 (inositol phosphosphingolipid-phospholipase C), the yeast homologue of neutral sphingomyelinases

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