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The role of proteosome-mediated proteolysis in modulating potentially harmful transcription factor activity in Saccharomyces cerevisiae.

Bonzanni N, Zhang N, Oliver SG, Fisher J - Bioinformatics (2011)

Bottom Line: Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones.Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast. jasmin.fisher@microsoft.com

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, De Boelelaan 1081a, 1081 HV Amsterdam, The Netherlands.

ABSTRACT

Motivation: The appropriate modulation of the stress response to variable environmental conditions is necessary to maintain sustained viability in Saccharomyces cerevisiae. Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.

Results: Prompted by qualitative modeling of the nutrient starvation response in yeast, we investigated in vivo the effect of proteolysis after nutrient starvation showing that, for the Gis1 transcription factor at least, proteasome-mediated control is crucial for a rapid return to growth. Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones. Furthermore, inhibiting proteasome activity tends to increase the expression of genes induced during the Environmental Stress Response more than those in the rest of the genome. Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast.

Contact: jasmin.fisher@microsoft.com

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Related in: MedlinePlus

Model of nutrient starvation response in yeast. (A) Diagrammatic model depicting the proteolytic control over Gis1 and the regulation of Rim15 by TOR, PKA and Pho80/Pho85. (B) Partial formal model of nutrient starvation response. Ovals=nodes that represent ‘places’—proteins (e.g. PKA, Rim15, Gis1) and genes (PDS and STRE); colored squares=interactions. Arcs ending with an arrowhead (in blue) represent positive interactions (e.g. activations), while arcs ending with bars (in red) represent negative interactions (e.g. inhibitions). Note that if multiple arrows target the same square, all the sources are required at the same time. Dashed lines represent the interaction responsible for the discrepancy between the modeled and observed behaviors.
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Figure 1: Model of nutrient starvation response in yeast. (A) Diagrammatic model depicting the proteolytic control over Gis1 and the regulation of Rim15 by TOR, PKA and Pho80/Pho85. (B) Partial formal model of nutrient starvation response. Ovals=nodes that represent ‘places’—proteins (e.g. PKA, Rim15, Gis1) and genes (PDS and STRE); colored squares=interactions. Arcs ending with an arrowhead (in blue) represent positive interactions (e.g. activations), while arcs ending with bars (in red) represent negative interactions (e.g. inhibitions). Note that if multiple arrows target the same square, all the sources are required at the same time. Dashed lines represent the interaction responsible for the discrepancy between the modeled and observed behaviors.

Mentions: In order to investigate the consistency and explanatory power of the available knowledge about the nutrient starvation response in yeast, we have constructed a dynamic computational model based on Petri nets (Reisig and Rozenberg, 1998). Petri nets can be depicted as graphs that contain two kinds of nodes: places, which represent resources and correspond to proteins and genes, and transitions, which represent interactions between places. Interactions can be either activations or inhibitions (Fig. 1B) and, during the course of the execution, each resource can change its state (in a Boolean fashion) from active to inactive (and vice versa) based on the surrounding interactions. Given a network topology, it is possible to execute the model and compare its behavior with the one observed empirically.Fig. 1.


The role of proteosome-mediated proteolysis in modulating potentially harmful transcription factor activity in Saccharomyces cerevisiae.

Bonzanni N, Zhang N, Oliver SG, Fisher J - Bioinformatics (2011)

Model of nutrient starvation response in yeast. (A) Diagrammatic model depicting the proteolytic control over Gis1 and the regulation of Rim15 by TOR, PKA and Pho80/Pho85. (B) Partial formal model of nutrient starvation response. Ovals=nodes that represent ‘places’—proteins (e.g. PKA, Rim15, Gis1) and genes (PDS and STRE); colored squares=interactions. Arcs ending with an arrowhead (in blue) represent positive interactions (e.g. activations), while arcs ending with bars (in red) represent negative interactions (e.g. inhibitions). Note that if multiple arrows target the same square, all the sources are required at the same time. Dashed lines represent the interaction responsible for the discrepancy between the modeled and observed behaviors.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117362&req=5

Figure 1: Model of nutrient starvation response in yeast. (A) Diagrammatic model depicting the proteolytic control over Gis1 and the regulation of Rim15 by TOR, PKA and Pho80/Pho85. (B) Partial formal model of nutrient starvation response. Ovals=nodes that represent ‘places’—proteins (e.g. PKA, Rim15, Gis1) and genes (PDS and STRE); colored squares=interactions. Arcs ending with an arrowhead (in blue) represent positive interactions (e.g. activations), while arcs ending with bars (in red) represent negative interactions (e.g. inhibitions). Note that if multiple arrows target the same square, all the sources are required at the same time. Dashed lines represent the interaction responsible for the discrepancy between the modeled and observed behaviors.
Mentions: In order to investigate the consistency and explanatory power of the available knowledge about the nutrient starvation response in yeast, we have constructed a dynamic computational model based on Petri nets (Reisig and Rozenberg, 1998). Petri nets can be depicted as graphs that contain two kinds of nodes: places, which represent resources and correspond to proteins and genes, and transitions, which represent interactions between places. Interactions can be either activations or inhibitions (Fig. 1B) and, during the course of the execution, each resource can change its state (in a Boolean fashion) from active to inactive (and vice versa) based on the surrounding interactions. Given a network topology, it is possible to execute the model and compare its behavior with the one observed empirically.Fig. 1.

Bottom Line: Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones.Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast. jasmin.fisher@microsoft.com

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, De Boelelaan 1081a, 1081 HV Amsterdam, The Netherlands.

ABSTRACT

Motivation: The appropriate modulation of the stress response to variable environmental conditions is necessary to maintain sustained viability in Saccharomyces cerevisiae. Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.

Results: Prompted by qualitative modeling of the nutrient starvation response in yeast, we investigated in vivo the effect of proteolysis after nutrient starvation showing that, for the Gis1 transcription factor at least, proteasome-mediated control is crucial for a rapid return to growth. Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones. Furthermore, inhibiting proteasome activity tends to increase the expression of genes induced during the Environmental Stress Response more than those in the rest of the genome. Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast.

Contact: jasmin.fisher@microsoft.com

Show MeSH
Related in: MedlinePlus