Dataset Information

Houser2012_pheromone_Ste12

ABSTRACT: This model is from the article: Positive roles for negative regulators in the mating response of yeast. Houser JR, Ford E, Nagiec MJ, Errede B, Elston TC. Mol Syst Biol 2012 June 5;8:586 22669614 , Abstract: All cells must detect and respond to changes in their environment, often through changes in gene expression. The yeast pheromone pathway has been extensively characterized, and is an ideal system for studying transcriptional regulation. Here we combine computational and experimental approaches to study transcriptional regulation mediated by Ste12, the key transcription factor in the pheromone response. Our mathematical model is able to explain multiple counterintuitive experimental results and led to several novel findings. First, we found that the transcriptional repressors Dig1 and Dig2 positively affect transcription by stabilizing Ste12. This stabilization through protein-protein interactions creates a large pool of Ste12 that is rapidly activated following pheromone stimulation. Second, we found that protein degradation follows saturating kinetics, explaining the long half-life of Ste12 in mutants expressing elevated amounts of Ste12. Finally, our model reveals a novel mechanism for robust perfect adaptation through protein-protein interactions that enhance complex stability. This mechanism allows the transcriptional response to act on a shorter time scale than upstream pathway activity.

SUBMITTER: John Houser

PROVIDER: MODEL1204040000 | BioModels | 2005-01-01

REPOSITORIES: BioModels

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	MODEL1204040000?filename=MODEL1204040000-biopax3.owl	Owl
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Positive roles for negative regulators in the mating response of yeast.

Houser John R JR Ford Eintou E Nagiec Michal J MJ Errede Beverly B Elston Timothy C TC

Molecular systems biology 20120605

All cells must detect and respond to changes in their environment, often through changes in gene expression. The yeast pheromone pathway has been extensively characterized, and is an ideal system for studying transcriptional regulation. Here we combine computational and experimental approaches to study transcriptional regulation mediated by Ste12, the key transcription factor in the pheromone response. Our mathematical model is able to explain multiple counterintuitive experimental results and l ...[more]

PMID: 22669614

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Project description:Fission yeast cells undergo sexual differentiation in response to nitrogen starvation. In this process haploid M and P cells first mate to form diploid zygotes, which subsequently enter meiosis and sporulate. Prior to mating, M cells secrete M-factor and P-cells secrete P-factor, and these diffusible mating pheromone can activate a signal transduction pathway in the opposite cell type. The pheromone response orchestrates mating and is also required for entry into meiosis. Here we use DNA microarrays to identify genes that are induced by M-factor in P cells and by P-factor in M-cells. The use of a cyr1 genetic background allowed us to study pheromone stimulation independently of nitrogen starvation. We identified a total of 163 genes that were consistently induced more than two-fold by pheromone stimulation. As expected, there was a substantial overlap between the genes induced by M- and P-factor. Surprisingly, we found that pheromone control extended to genes fulfilling their function well beyond the point of entry into meiosis, including numerous genes required for meiotic recombination. A direct comparison of the M- and P-factor induced expression pattern allowed us to identify cell-type specific transcripts, including three new M-specific genes and one new P-specific gene. Finally, our results support the notion that Ste11 is the key transcription factor activated by pheromone signalling. Keywords: dose response Gene expression profiling experiment in which gene expression in pheromone treated cultures was compared to that of untreated control cells. All cultures were growing exponentially in MSL minimal medium. S. pombe h+ cyr1- cells treated with M-factor mating pheromone for 2, 4 and 6 hrs respectively, were compared to non-treated cells. Similarly, S. pombe h- sax2- cyr1- cells treated with P-factor mating pheromone for 2, 4 and 6 hrs, were compared to non-treated cells. For identiofication of cell-type specific gene expression, h+ cyr1- cells were compaired to h+ sxa2- cyr1- cells. This was done both before pheromone treatment (0h/0h) and after 6 hours of pheromone treatment (6h/6h). RNA was extracted and subjected to cDNA expression profiling analysis using the established protocols (Xue et al, Yeast 21, 25-39, 2004).Data normalized with 'Lowess' per chip per spot normalization.

Project description:This a model from the article: A modelling approach to quantify dynamic crosstalk between the pheromone and the starvation pathway in baker's yeast. Schaber J, Kofahl B, Kowald A, Klipp E FEBS J.2006 Aug; 273(15):3520-33 16884493, Abstract: Cells must be able to process multiple information in parallel and, moreover, they must also be able to combine this information in order to trigger the appropriate response. This is achieved by wiring signalling pathways such that they can interact with each other, a phenomenon often called crosstalk. In this study, we employ mathematical modelling techniques to analyse dynamic mechanisms and measures of crosstalk. We present a dynamic mathematical model that compiles current knowledge about the wiring of the pheromone pathway and the filamentous growth pathway in yeast. We consider the main dynamic features and the interconnections between the two pathways in order to study dynamic crosstalk between these two pathways in haploid cells. We introduce two new measures of dynamic crosstalk, the intrinsic specificity and the extrinsic specificity. These two measures incorporate the combined signal of several stimuli being present simultaneously and seem to be more stable than previous measures. When both pathways are responsive and stimulated, the model predicts that (a) the filamentous growth pathway amplifies the response of the pheromone pathway, and (b) the pheromone pathway inhibits the response of filamentous growth pathway in terms of mitogen activated protein kinase activity and transcriptional activity, respectively. Among several mechanisms we identified leakage of activated Ste11 as the most influential source of crosstalk. Moreover, we propose new experiments and predict their outcomes in order to test hypotheses about the mechanisms of crosstalk between the two pathways. Studying signals that are transmitted in parallel gives us new insights about how pathways and signals interact in a dynamical way, e.g., whether they amplify, inhibit, delay or accelerate each other. This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.For more information see the terms of use.To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.