Ime1 and Ime2 Are Required for Pseudohyphal Growth of <i>Saccharomyces cerevisiae</i> on Nonfermentable Carbon Sources

Strudwick, Natalie; Brown, Max; Parmar, Vipul M.; Schröder, Martin

doi:10.1128/mcb.00390-10

Cited by 28 publications

(45 citation statements)

References 120 publications

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“…For example, in our experiments with the dimorphic ⌺1278b background, SUC2-lacZ reporter expression was significantly reduced in the ira and bcy1 mutants, whereas expression of constitutive Ras2 Val19 had no pronounced effect on SUC2 gene expression in the more commonly used W303 genetic background (81). ⌺1278b strains have an unusually high basal level of cAMP signaling (64,65), and their Snf1 pathway could therefore be more responsive to further increases in cAMP-PKA signaling. Another potential variable to consider is the rate of dephosphorylation of the relevant PKA sites by the cognate phosphatase(s), possibly including Reg1-Glc7 itself.…”

Section: Discussionmentioning

confidence: 96%

Protein Kinase A Contributes to the Negative Control of Snf1 Protein Kinase in Saccharomyces cerevisiae

et al. 2012

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Snf1 protein kinase regulates responses to glucose limitation and other stresses. Snf1 activation requires phosphorylation of its T-loop threonine by partially redundant upstream kinases (Sak1, Tos3, and Elm1). Under favorable conditions, Snf1 is turned off by Reg1-Glc7 protein phosphatase. The reg1 mutation causes increased Snf1 activation and slow growth. To identify new components of the Snf1 pathway, we searched for mutations that, like snf1, suppress reg1 for the slow-growth phenotype. In addition to mutations in genes encoding known pathway components (SNF1, SNF4, and SAK1), we recovered "fast" mutations, designated fst1 and fst2. Unusual morphology of the mutants in the ⌺1278b strains employed here helped us identify fst1 and fst2 as mutations in the RasGAP genes IRA1 and IRA2. Cells lacking Ira1, Ira2, or Bcy1, the negative regulatory subunit of cyclic AMP (cAMP)-dependent protein kinase A (PKA), exhibited reduced Snf1 pathway activation. Conversely, Snf1 activation was elevated in cells lacking the Gpr1 sugar receptor, which contributes to PKA signaling. We show that the Snf1-activating kinase Sak1 is phosphorylated in vivo on a conserved serine (Ser1074) within an ideal PKA motif. However, this phosphorylation alone appears to play only a modest role in regulation, and Sak1 is not the only relevant target of the PKA pathway. Collectively, our results suggest that PKA, which integrates multiple regulatory inputs, could contribute to Snf1 regulation under various conditions via a complex mechanism. Our results also support the view that, like its mammalian counterpart, AMP-activated protein kinase (AMPK), yeast Snf1 participates in metabolic checkpoint control that coordinates growth with nutrient availability.T he Snf1/AMP-activated protein kinase (AMPK) family is highly conserved in eukaryotes, and its members control responses to metabolic stress (reviewed in references 22, 23, and 26). Mammalian AMPK is activated by increased intracellular AMPto-ATP ratios under energy-depleting conditions, such as hypoglycemia and hypoxia. AMPK is also regulated by hormones that control whole-body metabolism, including leptin, adiponectin, and ghrelin. Activated AMPK functions to restore energy equilibrium by stimulating ATP-generating pathways and by inhibiting energy-consuming processes. Important functions of AMPK include stimulation of glucose uptake and fatty acid oxidation, as well as downregulation of protein synthesis and cell growth. Accordingly, defects in AMPK signaling have been linked to diseases from diabetes and obesity to cancer, making AMPK a promising target for activation with drugs (reviewed in references 15 and 21).In the yeast Saccharomyces cerevisiae, Snf1 protein kinase is the ortholog of mammalian AMPK. The most established role of Snf1 is to regulate responses to glucose limitation (for a review, see reference 26). As glucose levels decrease, Snf1 is activated and promotes the use of less preferred (alternative) carbon sources. Activation of Snf1 results from phosphorylation of its conserve...

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Section: Discussionmentioning

confidence: 96%

Protein Kinase A Contributes to the Negative Control of Snf1 Protein Kinase in Saccharomyces cerevisiae

et al. 2012

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“…In the SK1 yeast background, IME1, the master regulator of meiosis, is required for pseudohyphal growth on nonfermentable carbon sources (Kassir et al 1988;Strudwick et al 2010). Similar to FLO11 transcription, IME1 transcription is responsive to mating type, nitrogen, and carbon sources (Kassir et al 1988(Kassir et al , 2003.…”

Section: Ssn8 and Jdh2 Bypass The Requirement For Ime1 In Pseudohyphamentioning

confidence: 99%

“…Historically, studies focused on pseudohyphal growth have been performed in S1278B yeast strains, which execute meiotic differentiation at low efficiencies. More recently, the meiotic strain SK1 was shown to undergo pseudohyphal growth (Strudwick et al 2010), making it well suited for understanding the transitions from mitosis to either pseudohyphal growth or meiosis.…”

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confidence: 99%

Fine-Tuning of Histone H3 Lys4 Methylation During Pseudohyphal Differentiation by the CDK Submodule of RNA Polymerase II

Law

Ciccaglione

2014

Genetics

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Transcriptional regulation is dependent upon the interactions between the RNA pol II holoenzyme complex and chromatin. RNA pol II is part of a highly conserved multiprotein complex that includes the core mediator and CDK8 subcomplex. In Saccharomyces cerevisiae, the CDK8 subcomplex, composed of Ssn2p, Ssn3p, Ssn8p, and Srb8p, is thought to play important roles in mediating transcriptional control of stress-responsive genes. Also central to transcriptional control are histone post-translational modifications. Lysine methylation, dynamically balanced by lysine methyltransferases and demethylases, has been intensively studied, uncovering significant functions in transcriptional control. A key question remains in understanding how these enzymes are targeted during stress response. To determine the relationship between lysine methylation, the CDK8 complex, and transcriptional control, we performed phenotype analyses of yeast lacking known lysine methyltransferases or demethylases in isolation or in tandem with SSN8 deletions. We show that the RNA pol II CDK8 submodule components SSN8/SSN3 and the histone demethylase JHD2 are required to inhibit pseudohyphal growth-a differentiation pathway induced during nutrient limitation-under rich conditions. Yeast lacking both SSN8 and JHD2 constitutively express FLO11, a major regulator of pseudohyphal growth. Interestingly, deleting known FLO11 activators including FLO8, MSS11, MFG1, TEC1, SNF1, KSS1, and GCN4 results in a range of phenotypic suppression. Using chromatin immunoprecipitation, we found that SSN8 inhibits H3 Lys4 trimethylation independently of JHD2 at the FLO11 locus, suggesting that H3 Lys4 hypermethylation is locking FLO11 into a transcriptionally active state. These studies implicate the CDK8 subcomplex in finetuning H3 Lys4 methylation levels during pseudohyphal differentiation.?

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“…Diploid cells differentiate from their normal round growth pattern to an elongated cellular morphology in branched filaments of pseudohyphae that extend outwards from the colony and invade the agar, a response that is thought to facilitate foraging for nitrogen (17). Haploid cells produce a similar response, thought to occur in response to limiting carbon, by forming elongated filamentous cells that invade the agar immediately below the colony (36,40). These differentiation processes, known as pseudohyphal and haploid invasive growth, or collectively as filamentous growth, have similar genetic requirements, and the presence of different colony morphologies between haploids and diploids is primarily related to their distinct budding patterns (36).…”

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confidence: 99%

Cdk8 Regulates Stability of the Transcription Factor Phd1 To Control Pseudohyphal Differentiation of Saccharomyces cerevisiae

Raithatha

Lourenco

et al. 2012

Molecular and Cellular Biology

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The yeast Saccharomyces differentiates into filamentous pseudohyphae when exposed to a poor source of nitrogen in a process involving a collection of transcription factors regulated by nutrient signaling pathways. Phd1 is important for this process in that it regulates expression of most other transcription factors involved in differentiation and can induce filamentation on its own when overproduced. In this article, we show that Phd1 is an unstable protein whose degradation is initiated through phosphorylation by Cdk8 of the RNA polymerase II mediator subcomplex. Phd1 is stabilized by cdk8 disruption, and the naturally filamenting ⌺1278b strain was found to have a sequence polymorphism that eliminates a Cdk8 phosphorylation site, which both stabilizes the protein and contributes to enhanced differentiation. In nitrogen-starved cells, PHD1 expression is upregulated and the Phd1 protein becomes stabilized, which causes its accumulation during differentiation. PHD1 expression is partially dependent upon Ste12, which was also previously shown to be destabilized by Cdk8-dependent phosphorylations, but to a significantly smaller extent than Phd1. These observations demonstrate the central role that Cdk8 plays in initiation of differentiation. Cdk8 activity is inhibited in cells shifted to limiting nutrient conditions, and we argue that this effect drives the initiation of differentiation through stabilization of multiple transcription factors, including Phd1, that cause activation of genes necessary for filamentous response.

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Ime1 and Ime2 Are Required for Pseudohyphal Growth of Saccharomyces cerevisiae on Nonfermentable Carbon Sources

Cited by 28 publications

References 120 publications

Protein Kinase A Contributes to the Negative Control of Snf1 Protein Kinase in Saccharomyces cerevisiae

Protein Kinase A Contributes to the Negative Control of Snf1 Protein Kinase in Saccharomyces cerevisiae

Fine-Tuning of Histone H3 Lys4 Methylation During Pseudohyphal Differentiation by the CDK Submodule of RNA Polymerase II

Cdk8 Regulates Stability of the Transcription Factor Phd1 To Control Pseudohyphal Differentiation of Saccharomyces cerevisiae

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