Glucose Regulation of
            <i>Saccharomyces cerevisiae</i>
            Cell Cycle Genes

Newcomb, Laura L.; Diderich, Jasper A.; Slattery, Matthew; Heideman, Warren

doi:10.1128/ec.2.1.143-149.2003

Cited by 67 publications

(56 citation statements)

References 63 publications

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“…Our observations thus far are entirely consistent with previous studies showing that glucose is a potent inducer of CLN3 transcription (22). However, none of the well-known glucose or nutrientsignaling pathways, including cAMP-PKA, TOR, and various glucose transporters, seems to be required for glucose-induced CLN3 transcription (9,22,43). In contrast, the inhibition of glycolysis compromises glucose-induced CLN3 transcription, suggesting a downstream metabolite of glucose could be mediating its effects (9,22).…”

Section: Resultsmentioning

confidence: 99%

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Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

Shi

2013

Proc. Natl. Acad. Sci. U.S.A.

126

125

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In budding yeast cells, nutrient repletion induces rapid exit from quiescence and entry into a round of growth and division. The G1 cyclin CLN3 is one of the earliest genes activated in response to nutrient repletion. Subsequent to its activation, hundreds of cellcycle genes can then be expressed, including the cyclins CLN1/2 and CLB5/6. Although much is known regarding how CLN3 functions to activate downstream targets, the mechanism through which nutrients activate CLN3 transcription in the first place remains poorly understood. Here we show that a central metabolite of glucose catabolism, acetyl-CoA, induces CLN3 transcription by promoting the acetylation of histones present in its regulatory region. Increased rates of acetyl-CoA synthesis enable the Gcn5p-containing Spt-AdaGcn5-acetyltransferase transcriptional coactivator complex to catalyze histone acetylation at the CLN3 locus alongside ribosomal and other growth genes to promote entry into the cell division cycle.growth control | metabolism | epigenetics T he most basic building blocks of biological organisms are smallmolecule metabolites. In recent years, there has been renewed interest in understanding how the fundamental processes of cell growth and proliferation are coordinated with cellular metabolism. Nutrient-starved yeast cells arrest in a quiescent, or G0, phase of the cell division cycle. Addition of nutrients stimulates exit from the G0 and transition into the G1 phase, and then ∼800 genes are periodically transcribed as a function of the cell cycle (1, 2). CLN3 is observed to be one of the earliest genes transcribed within this set (1-3). Cln3p regulates G1 length by coordinating growth and division and may influence cell size when passing Start, the point at which cells commit to division (4-7). In cln3Δ mutants, cells become larger and stay in the G1 phase longer, resulting in decreased growth and budding rates compared with WT (8, 9) (Fig. S1). Following CLN3 activation, the G1 transcription complexes Swi4p-Swi6p (SBF) and Mbp1-Swi6p (MBF) can be activated by CLN3/CDC28-catalyzed phosphorylation of the SBF inhibitor Whi5p (10-12), and other unknown mechanisms, to enable transcription of over 200 downstream cell-cycle genes (13), including CLN1/2 and CLB5/6. Cln1p and Cln2p can then further enhance SBF-and MBF-dependent G1 transcription through positive feedback mechanisms (14)(15)(16)(17)(18)(19)(20).Although many studies have focused on the mechanisms by which Cln3p regulates G1 transcription, the mechanisms that lead to transcriptional activation of CLN3 itself still remain unresolved. Since the discovery of CLN3 more than 20 y ago (6, 7), the gene and its encoded protein have been reported to be regulated at multiple levels. At the transcriptional level, CLN3 is activated by glucose (21, 22), which is reportedly mediated by Azf1p, a zinc-finger transcription factor (23). Following transcription, CLN3 mRNA availability is regulated by a RNAbinding protein, Whi3p (24). At the translational level, CLN3 is regulated by TOR (target of rapamyc...

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Section: Resultsmentioning

confidence: 99%

“…Cln3p regulates G1 length by coordinating growth and division and may influence cell size when passing Start, the point at which cells commit to division (4)(5)(6)(7). In cln3Δ mutants, cells become larger and stay in the G1 phase longer, resulting in decreased growth and budding rates compared with WT (8,9) (Fig. S1).…”

mentioning

confidence: 99%

Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

Shi

2013

Proc. Natl. Acad. Sci. U.S.A.

126

125

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“…Because immobilized yeast vigorously ferments glucose during prolonged culture, it has been used for ethanol production, reportedly attaining, relative to planktonic cells, >10-fold increases in volumetric ethanol productivity at high substrate concentrations (65). However, whereas high glycolytic flux typically triggers expression of genes required to pass through G1 (66), immobilized fermentative yeast does not respond to this signal. Indeed, RAS1, which encodes a component of the RAS/cAMP/PKA glucosesignaling pathway, is down-regulated in immobilized relative to planktonic cells, and the gene encoding the transcriptional regulator Rpi1, which acts antagonistically to RAS/cAMP/PKA, is up-regulated (Fig.…”

Section: Two-class Sam Reveals Immobilization-specific Changes In Genmentioning

confidence: 99%

Uncoupling reproduction from metabolism extends chronological lifespan in yeast

Nagarajan

Kruckeberg

Schmidt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Studies of replicative and chronological lifespan in Saccharomyces cerevisiae have advanced understanding of longevity in all eukaryotes. Chronological lifespan in this species is defined as the agedependent viability of nondividing cells. To date this parameter has only been estimated under calorie restriction, mimicked by starvation. Because postmitotic cells in higher eukaryotes often do not starve, we developed a model yeast system to study cells as they age in the absence of calorie restriction. Yeast cells were encapsulated in a matrix consisting of calcium alginate to form ∼3 mm beads that were packed into bioreactors and fed ad libitum. Under these conditions cells ceased to divide, became heat shock and zymolyase resistant, yet retained high fermentative capacity. Over the course of 17 d, immobilized yeast cells maintained >95% viability, whereas the viability of starving, freely suspended (planktonic) cells decreased to <10%. Immobilized cells exhibited a stable pattern of gene expression that differed markedly from growing or starving planktonic cells, highly expressing genes in glycolysis, cell wall remodeling, and stress resistance, but decreasing transcription of genes in the tricarboxylic acid cycle, and genes that regulate the cell cycle, including master cyclins CDC28 and CLN1. Stress resistance transcription factor MSN4 and its upstream effector RIM15 are conspicuously up-regulated in the immobilized state, and an immobilized rim15 knockout strain fails to exhibit the long-lived, growth-arrested phenotype, suggesting that altered regulation of the Rim15-mediated nutrient-sensing pathway plays an important role in extending yeast chronological lifespan under calorie-unrestricted conditions. cell longevity | Ca-alginate encapsulation U nicellular microbes senesce and die (for reviews, see refs.

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“…Further, it seems that the bottleneck in the upper glycolysis in PGI and PFK results in a smaller flux of carbon downstream, which resembles a deletion of either of the genes PGI1, PFK1, or PFK2 (33, 34). Newcomb et al (35) have studied the relation of flux through glycolysis to the expression of genes encoding for cell cycle regulatory proteins CLN3, BCK2, and CDC28, whose expression causes a passage from phase G 1 (growth 1) into S phase (start). They found that deletion of either gene encoding for PFKe blocks glucose induction of CLN3, BCK2, and CDC28, resulting in a prolonged G 1 and thus slower growth (35).…”

Section: Figmentioning

confidence: 99%

“…Newcomb et al (35) have studied the relation of flux through glycolysis to the expression of genes encoding for cell cycle regulatory proteins CLN3, BCK2, and CDC28, whose expression causes a passage from phase G 1 (growth 1) into S phase (start). They found that deletion of either gene encoding for PFKe blocks glucose induction of CLN3, BCK2, and CDC28, resulting in a prolonged G 1 and thus slower growth (35). In our setup, the expression of cell cycle-related genes CLN3 and CDC28 was also decreased in the lower growth rates in elevated initial mannose concentrations.…”

Section: Figmentioning

confidence: 99%

Excess Mannose Limits the Growth of Phosphomannose Isomerase PMI40 Deletion Strain of Saccharomyces cerevisiae

Pitkänen¹,

Törmä

Alff³

et al. 2004

Journal of Biological Chemistry

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Phosphomannose isomerase (PMI40) catalyzes the conversion between fructose 6-phosphate and mannose 6-phosphate and thus connects glycolysis, i.e. energy production and GDP-mannose biosynthesis or cell wall synthesis in Saccharomyces cerevisiae. After PMI40 deletion (pmi ؊ ) the cells were viable only if fed with extracellular mannose and glucose. In an attempt to force the GDP-mannose synthesis in the pmi ؊ strain by increasing the extracellular mannose concentrations, the cells showed significantly reduced growth rates without any alterations in the intracellular GDPmannose levels. To reveal the mechanisms resulting in reduced growth rates, we measured genome-wide gene expression levels, several metabolite concentrations, and selected in vitro enzyme activities in central metabolic pathways. The increasing of the initial mannose concentration led to an increase in the mannose 6-phosphate concentration, which inhibited the activity of the second enzyme in glycolysis, i.e. phosphoglucose isomerase converting glucose 6-phosphate to fructose 6-phosphate. As a result of this limitation, the flux through glycolysis was decreased as was the median expression of the genes involved in glycolysis. The expression levels of RAP1, a transcription factor involved in the regulation of the mRNA levels of several enzymes in glycolysis, as well as those of cell cycle regulators CDC28 and CLN3, decreased concomitantly with the growth rates and expression of many genes encoding for enzymes in glycolysis.Phosphomannose isomerase enzyme (PMIe) 1 catalyzes the interconversion of fructose 6-phosphate (Fru-6-P) in glycolysis to mannose 6-phosphate (Man-6-P) through a mannose pathway. In the eukaryotic model organism, yeast Saccharomyces cerevisiae, phosphomannose isomerase is encoded by the PMI40 gene (1). In a PMI40 deletion strain (pmi Ϫ ), the synthesis of Man-6-P from Fru-6-P is not possible, disabling the growth of such a strain on medium without mannose. The inability to grow, caused by defective glycosylation of a temperature-sensitive pmi40 mutant of S. cerevisiae, and repairing the defects by addition of mannose to the growth medium have been described previously (2). In humans PMIe deficiency is the cause of carbohydrate-deficient glycoprotein syndrome type Ib, but the condition can be successfully treated by mannose administration (3). Man-6-P produced either from Fru-6-P or mannose serves as a precursor for the de novo biosynthesis of GDP-mannose. Man-6-P is converted to mannose 1-phosphate (Man-1-P) by phosphomannomutase encoded by SEC53. Subsequently, Man-1-P is ligated with the guanosine 5-triphosphate molecule (GTP) to form GDP-mannose by Man-1-P guanylyltransferase encoded by PSA1 (4). The de novo formation of the purine ring of GTP, required for the biosynthesis of GDPmannose, starts from ribose 5-phosphate in the pentose phosphate pathway and requires also 3-phosphoglycerate in the glycolysis as a precursor. Taken together, the biosynthesis of GTP is more complex than the mannose pathway (4). GDPmannose is needed in ...

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Glucose Regulation of Saccharomyces cerevisiae Cell Cycle Genes

Cited by 67 publications

References 63 publications

Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

Uncoupling reproduction from metabolism extends chronological lifespan in yeast

Excess Mannose Limits the Growth of Phosphomannose Isomerase PMI40 Deletion Strain of Saccharomyces cerevisiae

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