Caffeine extends yeast lifespan by targeting TORC1

Wanke, Valeria; Cameroni, Elisabetta; Uotila, Aino; Piccolis, Manuele; Urban, Jörg; Loewith, Robbie; Virgilio, Claudio De

doi:10.1111/j.1365-2958.2008.06292.x

Cited by 185 publications

(210 citation statements)

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“…We suggest that one such function is the inhibition of Msn2/4, because deletion of these two genes completely reverses the As(III)-sensitivity phenotype of tor1 cells (Figure 6). Consistent with this idea, previous work has implicated TORC1 as a negative regulator of Msn2/4 (Beck and Hall, 1999), at least partly acting through Sch9, which has recently been shown to downregulate several Msn2/4 target genes (Urban et al, 2007) and also directly regulates Rim15, a protein kinase involved in Msn2/4 regulation (Wanke et al, 2008). TORC1 may well have other functions that promote growth in the presence of As(III).…”

Section: The Complex Role Of Torc1 In Arsenic Resistancesupporting

confidence: 59%

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Hosiner

Lempiäinen

Reiter³

et al. 2009

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The conserved Target Of Rapamycin (TOR) growth control signaling pathway is a major regulator of genes required for protein synthesis. The ubiquitous toxic metalloid arsenic, as well as mercury and nickel, are shown here to efficiently inhibit the rapamycin-sensitive TORC1 (TOR complex 1) protein kinase. This rapid inhibition of the TORC1 kinase is demonstrated in vivo by the dephosphorylation and inactivation of its downstream effector, the yeast S6 kinase homolog Sch9. Arsenic, mercury, and nickel cause reduction of transcription of ribosome biogenesis genes, which are under the control of Sfp1, a TORC1-regulated transcriptional activator. We report that arsenic stress deactivates Sfp1 as it becomes dephosphorylated, dissociates from chromatin, and exits the nucleus. Curiously, whereas loss of SFP1 function leads to increased arsenic resistance, absence of TOR1 or SCH9 has the opposite effect suggesting that TORC1 has a role beyond down-regulation of Sfp1. Indeed, we show that arsenic activates the transcription factors Msn2 and Msn4 both of which are targets of TORC1 and protein kinase A (PKA). In contrast to TORC1, PKA activity is not repressed during acute arsenic stress. A normal level of PKA activity might serve to dampen the stress response since hyperactive Msn2 will decrease arsenic tolerance. Thus arsenic toxicity in yeast might be determined by the balance between chronic activation of general stress factors in combination with lowered TORC1 kinase activity. INTRODUCTIONThe transition metal arsenic has a long history of human exploitation as both a poison and a medicine. In more recent times EhrlichЈs discovery of the antisyphilitic drug arsphenamine (also known as salvarsan) by systematic chemical modification of arsenic derivatives marked the beginning of modern pharmaceutical research. Arsenic trioxide (ATO) is used today in cancer treatment (Evens et al., 2004;Lu et al., 2007;Wang and Chen, 2008).Exposure to arsenic evokes a broad spectrum of cellular reactions in Saccharomyces cerevisiae Haugen et al., 2004;Jin, 2008;Thorsen et al., 2007) and in higher eukaryotes (Salnikow and Zhitkovich, 2008). A number of mechanisms exist for detoxification, probably because arsenic has always been widespread in the environment. These involve reduction of influx through the aquaglyceroporin Fps1p Thorsen et al., 2006); sequestration into the vacuole in the form of glutathione conjugates, metallothionein, and other metal/protein complexes; and active extrusion (Ghosh et al., 1999). In yeast, genome-wide analysis of the transcription patterns in response to arsenic revealed a complex network of transcription factors controlling the expression of several hundred genes (Haugen et al., 2004;Wysocki et al., 2004;Thorsen et al., 2007). Mitogen-activated protein kinases mediate protective responses involving AP-1-and AP-1-like transcription factors in higher eukaryotes and in fungi (Cavigelli et al., 1996;Rodriguez-Gabriel and Russell, 2005;Thorsen et al., 2006).The mechanisms by which arsenic might influence signalin...

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Section: The Complex Role Of Torc1 In Arsenic Resistancesupporting

confidence: 59%

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Hosiner

Lempiäinen

Reiter³

et al. 2009

MBoC

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“…Best studied is its role in the regulation of the protein kinase Rim15, which in turn controls the expression of stress-responsive genes through the transcriptional activators Gis1 and Msn2/4 that, respectively, bind to the PDS and STRE elements (Crauwels et al 1997a;Pedruzzi et al 2003;Cameroni et al 2004;Roosen et al 2005). Sch9 phosphorylates Rim15 at Ser 1061 in vitro and this phosphorylation event is necessary for normal cytoplasmic retention of Rim15 (Pedruzzi et al 2003;Wanke et al 2008). Mechanistically, phosphorylated Ser 1061 in Rim15, together with phosphorylated Thr 1075 by the Pho85-Pho80 kinase complex (see also below), may allow Rim15 to engage in binding the two monomeric subunits within a single 14-3-3 (Bmh2) protein dimer (Wanke et al , 2008 and thereby guarantee optimal sequestration of Rim15 in the cytoplasm (Fig.…”

Section: The Protein Kinase Sch9mentioning

confidence: 97%

“…Sch9 phosphorylates Rim15 at Ser 1061 in vitro and this phosphorylation event is necessary for normal cytoplasmic retention of Rim15 (Pedruzzi et al 2003;Wanke et al 2008). Mechanistically, phosphorylated Ser 1061 in Rim15, together with phosphorylated Thr 1075 by the Pho85-Pho80 kinase complex (see also below), may allow Rim15 to engage in binding the two monomeric subunits within a single 14-3-3 (Bmh2) protein dimer (Wanke et al , 2008 and thereby guarantee optimal sequestration of Rim15 in the cytoplasm (Fig. 5).…”

Section: The Protein Kinase Sch9mentioning

confidence: 98%

“…Here, TORC1 has a dual control. On the one hand, it prevents nuclear translocation of the protein kinase Rim15, thereby ensuring that this kinase is maintained inactive through PKA-mediated phosphorylation (Pedruzzi et al 2003;Urban et al 2007;Wanke et al 2008). Since this control involves Sch9, it will be discussed in more detail in the section below.…”

Section: Rapamycin-sensitive Signalling Via Torc1mentioning

confidence: 99%

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Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

et al. 2010

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Cells of all living organisms contain complex signal transduction networks to ensure that a wide range of physiological properties are properly adapted to the environmental conditions. The fundamental concepts and individual building blocks of these signalling networks are generally well-conserved from yeast to man; yet, the central role that growth factors and hormones play in the regulation of signalling cascades in higher eukaryotes is executed by nutrients in yeast. Several nutrient-controlled pathways, which regulate cell growth and proliferation, metabolism and stress resistance, have been defined in yeast. These pathways are integrated into a signalling network, which ensures that yeast cells enter a quiescent, resting phase (G 0 ) to survive periods of nutrient scarceness and that they rapidly resume growth and cell proliferation when nutrient conditions become favourable again. A series of well-conserved nutrient-sensory protein kinases perform key roles in this signalling network: i.e. Snf1, PKA, Tor1 and Tor2, Sch9 and Pho85-Pho80. In this review, we provide a comprehensive overview on the current understanding of the signalling processes mediated via these kinases with a particular focus on how these individual pathways converge to signalling networks that ultimately ensure the dynamic translation of extracellular nutrient signals into appropriate physiological responses.

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“…Indeed, ongoing research in the field continues to highlight promising compounds that warrant further study (10,134,135). A significant portion of this wealth of data is emerging from a program initiated in 2003 by the National Institute on Aging (NIA) to rigorously test pharmacological and dietary agents that may extend the longevity of mice (10,136) (http://www.nia.nih.gov/ResearchInformation/scient ificResources/CompoundsInTesting.htm).…”

Section: Discussionmentioning

confidence: 99%

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

Minor

Allard

Younts

et al. 2010

The Journals of Gerontology Series A: Biological Sciences and M

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The societal impact of obesity, diabetes, and other metabolic disorders continues to rise despite increasing evidence of their negative long-term consequences on health span, longevity, and aging. Unfortunately, dietary management and exercise frequently fail as remedies, underscoring the need for the development of alternative interventions to successfully treat metabolic disorders and enhance life span and health span. Using calorie restriction (CR)-which is well known to improve both health and longevity in controlled studies-as their benchmark, gerontologists are coming closer to identifying dietary and pharmacological therapies that may be applicable to aging humans. This review covers some of the more promising interventions targeted to affect pathways implicated in the aging process as well as variations on classical CR that may be better suited to human adaptation.

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Caffeine extends yeast lifespan by targeting TORC1

Abstract: Summary Dietary nutrient limitation (dietary restriction)

Cited by 185 publications

References 38 publications

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

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