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Dose response relationship in anti-stress gene regulatory networks.

Zhang Q, Andersen ME - PLoS Comput. Biol. (2006)

Bottom Line: Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis.Each phase relies on specific gain-changing events that come into play as stressor level increases.The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions.

View Article: PubMed Central - PubMed

Affiliation: Division of Computational Biology, CIIT Centers for Health Research, Research Triangle Park, North Carolina, United States of America. qzhang@ciit.org

ABSTRACT
To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.

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Simulation Results for the Anti-Electrophilic Gene Regulatory Network Model(A) Temporal changes in the levels of electrophile X, conjugation product GSX, GSH, Nrf2, GCL, and GST, in response to different stressor doses.(B) Steady-state dose response curves for the molecular species listed in (A). Dashed tangent lines originating from (−1, 0) were drawn to help visualizing curvature changes. One unit of external stressor level is equivalent to producing X at the basal production rate.
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pcbi-0030024-g011: Simulation Results for the Anti-Electrophilic Gene Regulatory Network Model(A) Temporal changes in the levels of electrophile X, conjugation product GSX, GSH, Nrf2, GCL, and GST, in response to different stressor doses.(B) Steady-state dose response curves for the molecular species listed in (A). Dashed tangent lines originating from (−1, 0) were drawn to help visualizing curvature changes. One unit of external stressor level is equivalent to producing X at the basal production rate.

Mentions: Our simulation indicated that the anti-electrophilic defense system launches a typical adaptive response when challenged continuously with electrophilic stresses (Figure 11A). The simulated dynamics is similar to experimental observations in a variety of cells exposed to many electrophiles, such as 4-hydroxy-2-nonenal (4-HNE) and 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) [41,42]. The electrophile X initially rises sharply, but after a few hours it settles at much lower steady-state levels. GSX follows a similar dynamic change, albeit it declines to steady states more slowly. In comparison, Nrf2, GCL, GS (unpublished data), and GST levels peak in a more delayed manner before leveling off. MRP, due to its long half-life (27 h in the current model), does not reach a steady state until a much later time (unpublished data). The level of intracellular GSH initially decreases as a result of consumption by electrophiles. But the downtrend is soon reversed as the expression level of GCL and GS increases. After a few hours, GSH surpasses its basal level and then peaks before settling down on elevated steady-state levels.


Dose response relationship in anti-stress gene regulatory networks.

Zhang Q, Andersen ME - PLoS Comput. Biol. (2006)

Simulation Results for the Anti-Electrophilic Gene Regulatory Network Model(A) Temporal changes in the levels of electrophile X, conjugation product GSX, GSH, Nrf2, GCL, and GST, in response to different stressor doses.(B) Steady-state dose response curves for the molecular species listed in (A). Dashed tangent lines originating from (−1, 0) were drawn to help visualizing curvature changes. One unit of external stressor level is equivalent to producing X at the basal production rate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808489&req=5

pcbi-0030024-g011: Simulation Results for the Anti-Electrophilic Gene Regulatory Network Model(A) Temporal changes in the levels of electrophile X, conjugation product GSX, GSH, Nrf2, GCL, and GST, in response to different stressor doses.(B) Steady-state dose response curves for the molecular species listed in (A). Dashed tangent lines originating from (−1, 0) were drawn to help visualizing curvature changes. One unit of external stressor level is equivalent to producing X at the basal production rate.
Mentions: Our simulation indicated that the anti-electrophilic defense system launches a typical adaptive response when challenged continuously with electrophilic stresses (Figure 11A). The simulated dynamics is similar to experimental observations in a variety of cells exposed to many electrophiles, such as 4-hydroxy-2-nonenal (4-HNE) and 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) [41,42]. The electrophile X initially rises sharply, but after a few hours it settles at much lower steady-state levels. GSX follows a similar dynamic change, albeit it declines to steady states more slowly. In comparison, Nrf2, GCL, GS (unpublished data), and GST levels peak in a more delayed manner before leveling off. MRP, due to its long half-life (27 h in the current model), does not reach a steady state until a much later time (unpublished data). The level of intracellular GSH initially decreases as a result of consumption by electrophiles. But the downtrend is soon reversed as the expression level of GCL and GS increases. After a few hours, GSH surpasses its basal level and then peaks before settling down on elevated steady-state levels.

Bottom Line: Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis.Each phase relies on specific gain-changing events that come into play as stressor level increases.The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions.

View Article: PubMed Central - PubMed

Affiliation: Division of Computational Biology, CIIT Centers for Health Research, Research Triangle Park, North Carolina, United States of America. qzhang@ciit.org

ABSTRACT
To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.

Show MeSH
Related in: MedlinePlus