Open Access

Glucose regulates transcription in yeast through a network of signaling pathways

Shadia Zaman, Soyeon I Lippman, Lisa Schneper, Noam Slonim, James R Broach

Author Affiliations

  1. Shadia Zaman1,,
  2. Soyeon I Lippman1,
  3. Lisa Schneper1,,
  4. Noam Slonim1,§ and
  5. James R Broach*,1
  1. 1 Department of Molecular Biology, Princeton University, Princeton, NJ, USA
  1. *Corresponding author. Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA. Tel.: +1 609 258 5981; Fax: +1 609 258 1975; E-mail: jbroach{at}
  • Present address: NIDDK, National Institutes of Health, Building 10, Room 9C‐103, Bethesda, MD 20892, USA

  • Present address: Department of Molecular Microbiology and Infectious Diseases, College of Medicine, Florida International University, Miami, FL 33199, USA

  • § Present address: IBM Haifa Research Labs, Haifa 31905, Israel

View Full Text

This article has a correction. Please see:


Addition of glucose to yeast cells increases their growth rate and results in a massive restructuring of their transcriptional output. We have used microarray analysis in conjunction with conditional mutations to obtain a systems view of the signaling network responsible for glucose‐induced transcriptional changes. We found that several well‐studied signaling pathways—such as Snf1 and Rgt—are responsible for specialized but limited responses to glucose. However, 90% of the glucose‐induced changes can be recapitulated by the activation of protein kinase A (PKA) or by the induction of PKB (Sch9). Blocking signaling through Sch9 does not interfere with the glucose response, whereas blocking signaling through PKA does. We conclude that both Sch9 and PKA regulate a massive, nutrient‐responsive transcriptional program promoting growth, but that they do so in response to different nutritional inputs. Moreover, activating PKA completely recapitulates the transcriptional growth program in the absence of any increase in growth or metabolism, demonstrating that activation of the growth program results solely from the cell's perception of its nutritional status.


The budding yeast Saccharomyces cerevisiae, similar to other unicellular microorganisms, has evolved to make optimum use of accessible nutrients and to adapt to nutritional deficiencies in a manner that maximizes survival. These behaviors require that yeast cells assess the amount and nature of available nutrients and modify their transcriptional, metabolic and developmental programs in response to that assessment. Saccharomyces uses glucose in preference to other fermentable sugars or oxidizable carbon compounds as a source for its energetic and anabolic needs. Accordingly, Saccharomyces has elaborated a complex, interlocking network of signaling pathways to assess the level of available glucose and to adjust its growth program in response to that assessment (Figure 8). Moreover, Saccharomyces adapts its growth rate, as well as the expression levels of a collection of growth‐rate specific genes, in proportion to glucose availability over a wide range of limiting glucose concentrations. In this report, we describe the results of a systems approach that allow us to precisely define the nature of the complex signaling network Saccharomyces uses to assess glucose availability. In addition, we show that Saccharomyces establishes its growth‐setting transcriptional program on the basis of its perception of available glucose rather than on its use of that resource.

Several signaling pathways have previously been associated with the glucose perception and response in yeast, although the relative contribution of each and the extent of overlap among them have not been resolved. To define the contributions of these pathways, we pursued a systems‐level epistasis analysis. Namely, we examined how much of the glucose response could be recapitulated by activating each of the pathways independently or in combination and, reciprocally, we asked how much of the glucose response was retained in the absence of one or more of the signaling pathways. These results were facilitated by the availability in yeast of genetic tools that allowed de novo activation or elimination of specific signaling pathways. We activated individual pathways by placing a key upstream component of the pathway under control of an inducible promoter that we could turn on with a gratuitous inducer. In many cases, we could instantaneously inactivate a pathway by inhibiting a key kinase intermediate by replacing the wild‐type kinase with one engineered to be uniquely sensitive to an AMP analog and then adding the analog to the strain concurrently with glucose addition. The advantage of using these analog‐sensitive kinases was that, although the kinase is completely inhibited after addition of the analog, the cells behave completely similar to wild type prior to the addition of the analog. As a consequence, we were not confounded by secondary effects attendant on loss of the kinase activity, as would be the case of using a strain simply deleted for the kinase.

The pathways previously implicated in glucose signaling in yeast are homologous to signaling pathways that play various role in glucose sensing and response in higher eukaryotes: (1) a Ras‐activated cAMP‐dependent protein kinase (PKA), (2) a TORC1‐regulated kinase, Sch9, homologous to mammalian PKB, (3) a heterotrimeric G protein, Gpa2, coupled to a heptahelical receptor, Gpr1, reported to be activated by glucose, (4) a glucose‐inhibited kinase, Snf1, homologous to mammalian AMP‐activated PK, (5) a transcriptional repressor, Rgt2, regulated by integral plasma membrane glucose sensors and (6) various transcription factors, Hap1–4, responsive to heme levels in the cell. To capture the output of glucose‐induced signaling, we measured the global transcriptional response of cells to glucose addition, in which the expression levels of more than 40% of all genes change significantly, and compared that with the global transcriptional response upon activation of individual pathways in the absence of glucose or inactivation of individual pathways concurrently with the addition of glucose. The results of one such experiment are shown in Figure 2D, in which the effect of glucose addition to wild‐type cells is compared with glucose addition to cells simultaneously with inactivation of Sch9 and PKA. The results indicate that most of the glucose response is eliminated in the absence of signaling through Sch9 and PKA, except for a residual repressive signal that is mediated predominated by the AMP‐activated kinase, Snf1, and a residual inductive signal, mediated predominated by the plasma membrane glucose sensors.

Figure 8 summarizes the glucose network that emerged from our studies. Most of the glucose signal proceeds through PKA. Although activation of Sch9, a TORC1‐regulated kinase, can recapitulate glucose signaling, Sch9 transmits only a small portion of the glucose signal. Rather, the overlap in response of Sch9 and PKA reflects a common effect of the glucose‐induced nutritional response and the TORC1‐mediated nitrogen source‐induced nutritional response. The Snf1 and Rgt2 pathways regulate a small number of functionally specialized genes, involved in alternate carbon source utilization and hexose transport, respectively. Finally, the heme‐regulated transcription factors provide a unique branch that regulates oxidative phosphorylation.

Several surprises emerged from these studies. First, although the apparent glucose receptor, Gpr1, participates in glucose‐regulated developmental programs, such as yeast–pseudohyphal transitions, it does not contribute at all to the acute transcriptional response of cells to glucose. Second, Sch9 regulates not only core growth and stress genes in response to nitrogen source, it also directly suppresses signaling through the Gpr1 pathway. This previously unrecognized cross‐talk may contribute to the integration of multiple signaling pathways underlying the cell's decision to differentiate into pseudohyphae. Finally, we found that the cell establishes a highly stereotypic growth‐promoting transcriptional program—enhancing mass accumulating potential and suppressing stress responses—not on the basis of the ability to use available nutrients but solely on its perception of availability of those nutrients. As a consequence, fooling the cell into thinking such nutrients are available creates a lethal condition as the cell's metabolic reprogramming does not match the nutrients actually available. This observation suggests a novel avenue of therapeutic control not only of microorganisms but also of cancer cells, which have clearly been reprogrammed for nutrient‐dependent rapid metabolism.

Mol Syst Biol. 5: 245

  • Received September 19, 2008.
  • Accepted January 7, 2009.
Creative Commons logo

This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

View Full Text