Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Up-regulation of the Cdc42 GTPase limits the replicative life span of budding yeast.

ABSTRACT: Cdc42, a conserved Rho GTPase, plays a central role in polarity establishment in yeast and animals. Cell polarity is critical for asymmetric cell division, and asymmetric cell division underlies replicative aging of budding yeast. Yet how Cdc42 and other polarity factors impact life span is largely unknown. Here we show by live-cell imaging that the active Cdc42 level is sporadically elevated in wild type during repeated cell divisions but rarely in the long-lived bud8 deletion cells. We find a novel Bud8 localization with cytokinesis remnants, which also recruit Rga1, a Cdc42 GTPase activating protein. Genetic analyses and live-cell imaging suggest that Rga1 and Bud8 oppositely impact life span likely by modulating active Cdc42 levels. An rga1 mutant, which has a shorter life span, dies at the unbudded state with a defect in polarity establishment. Remarkably, Cdc42 accumulates in old cells, and its mild overexpression accelerates aging with frequent symmetric cell divisions, despite no harmful effects on young cells. Our findings implicate that the interplay among these positive and negative polarity factors limits the life span of budding yeast.

SUBMITTER: Kang PJ

PROVIDER: S-EPMC9250358 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Implication of Ca2+ in the regulation of replicative life span of budding yeast.

Project description:In eukaryotic cells, Ca(2+)-triggered signaling pathways are used to regulate a wide variety of cellular processes. Calcineurin, a highly conserved Ca(2+)/calmodulin-dependent protein phosphatase, plays key roles in the regulation of diverse biological processes in organisms ranging from yeast to humans. We isolated a mutant of the SIR3 gene, implicated in the regulation of life span, as a suppressor of the Ca(2+) sensitivity of zds1Δ cells in the budding yeast Saccharomyces cerevisiae. Therefore, we investigated a relationship between Ca(2+) signaling and life span in yeast. Here we show that Ca(2+) affected the replicative life span (RLS) of yeast. Increased external and intracellular Ca(2+) levels caused a reduction in their RLS. Consistently, the increase in calcineurin activity by either the zds1 deletion or the constitutively activated calcineurin reduced RLS. Indeed, the shortened RLS of zds1Δ cells was suppressed by the calcineurin deletion. Further, the calcineurin deletion per se promoted aging without impairing the gene silencing typically observed in short-lived sir mutants, indicating that calcineurin plays an important role in a regulation of RLS even under normal growth condition. Thus, our results indicate that Ca(2+) homeostasis/Ca(2+) signaling are required to regulate longevity in budding yeast.

| S-EPMC3190675 | biostudies-literature

Regulation of Cdc42 polarization by the Rsr1 GTPase and Rga1, a Cdc42 GTPase-activating protein, in budding yeast.

Project description:Cdc42 plays a central role in establishing polarity in yeast and animals, yet how polarization of Cdc42 is achieved in response to spatial cues is poorly understood. Using live-cell imaging, we found distinct dynamics of Cdc42 polarization in haploid budding yeast in correlation with two temporal steps of the G1 phase. The position at which the Cdc42-GTP cluster develops changes rapidly around the division site during the first step but becomes stabilized in the second step, suggesting that an axis of polarized growth is determined in mid G1. Cdc42 polarization in the first step and its proper positioning depend on Rsr1 and its GTPase-activating protein (GAP) Bud2. Interestingly, Rga1, a Cdc42 GAP, exhibits transient localization to a site near the bud neck and to the division site during cytokinesis and G1, and this temporal change of Rga1 distribution is necessary for determination of a proper growth site. Mathematical modeling suggests that a proper axis of Cdc42 polarization in haploid cells might be established through a biphasic mechanism involving sequential positive feedback and transient negative feedback.

| S-EPMC4457026 | biostudies-literature

The Rsr1/Bud1 GTPase interacts with itself and the Cdc42 GTPase during bud-site selection and polarity establishment in budding yeast.

Project description:Cell polarization occurs along a single axis that is generally determined in response to spatial cues. In budding yeast, the Rsr1 GTPase and its regulators direct the establishment of cell polarity at the proper cortical location in response to cell type-specific cues. Here we use a combination of in vivo and in vitro approaches to understand how Rsr1 polarization is established. We find that Rsr1 associates with itself in a spatially and temporally controlled manner. The homotypic interaction and localization of Rsr1 to the mother-bud neck and to the subsequent division site are dependent on its GDP-GTP exchange factor Bud5. Analyses of rsr1 mutants suggest that Bud5 recruits Rsr1 to these sites and promotes the homodimer formation. Rsr1 also exhibits heterotypic interaction with the Cdc42 GTPase in vivo. We show that the polybasic region of Rsr1 is necessary for the efficient homotypic and heterotypic interactions, selection of a proper growth site, and polarity establishment. Our findings thus suggest that dimerization of GTPases may be an efficient mechanism to set up cellular asymmetry.

| S-EPMC2929994 | biostudies-literature

Pterocarpus marsupium extract extends replicative lifespan in budding yeast.

Project description:As the molecular mechanisms of biological aging become better understood, there is growing interest in identifying interventions that target those mechanisms to promote extended health and longevity. The budding yeast Saccharomyces cerevisiae has served as a premier model organism for identifying genetic and molecular factors that modulate cellular aging and is a powerful system in which to evaluate candidate longevity interventions. Here we screened a collection of natural products and natural product mixtures for effects on the growth rate, mTOR-mediated growth inhibition, and replicative lifespan. No mTOR inhibitory activity was detected, but several of the treatments affected growth rate and lifespan. The strongest lifespan shortening effects were observed for green tea extract and berberine. The most robust lifespan extension was detected from an extract of Pterocarpus marsupium and another mixture containing Pterocarpus marsupium extract. These findings illustrate the utility of the yeast system for longevity intervention discovery and identify Pterocarpus marsupium extract as a potentially fruitful longevity intervention for testing in higher eukaryotes.

| S-EPMC8599564 | biostudies-literature

Parallel Actin-Independent Recycling Pathways Polarize Cdc42 in Budding Yeast.

Project description:The highly conserved Rho-family GTPase Cdc42 is an essential regulator of polarity in many different cell types. During polarity establishment, Cdc42 becomes concentrated at a cortical site, where it interacts with downstream effectors to orient the cytoskeleton along the front-back axis. To concentrate Cdc42, loss of Cdc42 by diffusion must be balanced by recycling to the front. In Saccharomyces cerevisiae, the guanine nucleotide dissociation inhibitor (GDI) Rdi1 recycles Cdc42 through the cytoplasm. Loss of Rdi1 slowed but did not eliminate Cdc42 accumulation at the front, suggesting the existence of other recycling pathways. One proposed pathway involves actin-directed trafficking of vesicles carrying Cdc42 to the front. However, we found no role for F-actin in Cdc42 concentration, even in rdi1Δ cells. Instead, Cdc42 was still able to exchange between the membrane and cytoplasm in rdi1Δ cells, albeit at a reduced rate. Membrane-cytoplasm exchange of GDP-Cdc42 was faster than that of GTP-Cdc42, and computational modeling indicated that such exchange would suffice to promote polarization. We also uncovered a novel role for the Cdc42-directed GTPase-activating protein (GAP) Bem2 in Cdc42 polarization. Bem2 was known to act in series with Rdi1 to promote recycling of Cdc42, but we found that rdi1Δ bem2Δ mutants were synthetically lethal, suggesting that they also act in parallel. We suggest that GAP activity cooperates with the GDI to counteract the dissipative effect of a previously unappreciated pathway whereby GTP-Cdc42 escapes from the polarity site through the cytoplasm.

| S-EPMC5956535 | biostudies-literature

Increased respiration in the sch9Delta mutant is required for increasing chronological life span but not replicative life span.

Project description:Loss of the protein kinase Sch9p increases both the chronological life span (CLS) and the replicative life span (RLS) of Saccharomyces cerevisiae by mimicking calorie restriction, but the physiological consequences of SCH9 deletion are poorly understood. By transcriptional profiling of an sch9Delta mutant, we show that mitochondrial electron transport chain genes are upregulated. Accordingly, protein levels of electron transport chain subunits are increased and the oxygen consumption rate is enhanced in the sch9Delta mutant. Deletion of HAP4 and CYT1, both of which are essential for respiration, revert the sch9Delta mutant respiratory rate back to a lower-than-wild-type level. These alterations of the electron transport chain almost completely blocked CLS extension by the sch9Delta mutation but had a minor impact on the RLS. SCH9 thus negatively regulates the CLS and RLS through inhibition of respiratory genes, but a large part of its action on life span seems to be respiration independent and might involve increased resistance to stress. Considering that TOR1 deletion also increases respiration and that Sch9p is a direct target of TOR signaling, we propose that SCH9 is one of the major effectors of TOR repression of respiratory activity in glucose grown cells.

| S-EPMC2446671 | biostudies-literature

Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling.

Project description:Here we show that yeast strains with reduced target of rapamycin (TOR) signaling have greater overall mitochondrial electron transport chain activity during growth that is efficiently coupled to ATP production. This metabolic alteration increases mitochondrial membrane potential and reactive oxygen species (ROS) production, which we propose supplies an adaptive signal during growth that extends chronological life span (CLS). In strong support of this concept, uncoupling respiration during growth or increasing expression of mitochondrial manganese superoxide dismutase significantly curtails CLS extension in tor1? strains, and treatment of wild-type strains with either rapamycin (to inhibit TORC1) or menadione (to generate mitochondrial ROS) during growth is sufficient to extend CLS. Finally, extension of CLS by reduced TORC1/Sch9p-mitochondrial signaling occurs independently of Rim15p and is not a function of changes in media acidification/composition. Considering the conservation of TOR-pathway effects on life span, mitochondrial ROS signaling may be an important mechanism of longevity regulation in higher organisms.

| S-EPMC3110654 | biostudies-literature

Impaired cohesion and homologous recombination during replicative aging in budding yeast.

Project description:The causal relationship between genomic instability and replicative aging is unclear. We reveal here that genomic instability at the budding yeast ribosomal DNA (rDNA) locus increases during aging, potentially due to the reduced cohesion that we uncovered during aging caused by the reduced abundance of multiple cohesin subunits, promoting increased global chromosomal instability. In agreement, cohesion is lost during aging at other chromosomal locations in addition to the rDNA, including centromeres. The genomic instability in old cells is exacerbated by a defect in DNA double-strand break (DSB) repair that we uncovered in old yeast. This was due to limiting levels of key homologous recombination proteins because overexpression of Rad51 or Mre11 reduced the accumulation of DSBs and largely restored DSB repair in old cells. We propose that increased rDNA instability and the reduced DSB repair capacity of old cells contribute to the progressive accumulation of global chromosomal DNA breaks, where exceeding a threshold of genomic DNA damage ends the replicative life span.

| S-EPMC5810620 | biostudies-literature

Bud3 activates Cdc42 to establish a proper growth site in budding yeast.

Project description:Cell polarization occurs along a single axis that is generally determined by a spatial cue, yet the underlying mechanism is poorly understood. Using biochemical assays and live-cell imaging, we show that cell polarization to a proper growth site requires activation of Cdc42 by Bud3 in haploid budding yeast. Bud3 catalyzes the release of guanosine diphosphate (GDP) from Cdc42 and elevates intracellular Cdc42-guanosine triphosphate (GTP) levels in cells with inactive Cdc24, which has as of yet been the sole GDP-GTP exchange factor for Cdc42. Cdc42 is activated in two temporal steps in the G1 phase: the first depends on Bud3, whereas subsequent activation depends on Cdc24. Mutational analyses suggest that biphasic activation of Cdc42 in G1 is necessary for assembly of a proper bud site. Biphasic activation of Cdc42 or Rac GTPases may be a general mechanism for spatial cue-directed cell polarization in eukaryotes.

| S-EPMC4085707 | biostudies-literature

Cell integrity limits ploidy in budding yeast

Project description:Evidence suggests that increases in ploidy have occurred frequently in the evolutionary history of organisms, and can serve adaptive functions to specialized, somatic cells in multicellular organisms (Edgar & Orr-Weaver, 2001; Orr-Weaver, 2015; Van De Peer et al., 2017). However, the sudden multiplication of all chromosome content may present physiological challenges to the cells in which it occurs. Experimental studies have associated increases in ploidy with reduced cell survival and proliferation (Andalis et al., 2004; Fujiwara et al., 2005). To understand the physiological challenges that suddenly-increased chromosome content imposes on cells, we used S. cerevisiae cells to ask how much chromosomal DNA cells may contain, and what determines this limit. We generated polyploid cells using two distinct methods causing cells to undergo endoreplication and identified the maximum ploidy of these cells, 32-64C. We found that physical determinants that alleviate or exacerbate cell surface stress increase and decrease the limit to ploidy, respectively. We also used these cells to investigate gene expression changes associated with increased ploidy, and identified the repression of genes involved in ergosterol biosynthesis. We propose that ploidy is inherently limited by the impacts of growth in size, which accompany whole genome duplication, to cell surface integrity.

2024-12-03 | GSE275298 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data