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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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Dose Response Curves of Electrophile X versus Stressor under Various Disrupted Conditions(A) Effects of deregulation of Gclc, Gclm, Gs, and Gst genes by Nrf2. Deregulation was implemented by clamping mRNAs of respective genes at levels seen at the basal condition.(B) Effects of lack of Nrf2 autoregulation and/or GST functioning as a homodimer. Removal of Nrf2 autoregulation was implemented similarly as in (A); de-dimerization of GST was implemented by replacing the quadratic term in Reaction 44 with a linear term that left GST concentration at the basal condition unchanged.(C) Effects of product inhibition of GST-catalyzed reaction. For reduced GSX inhibition, Ki in Reaction 57 was increased to 850 μM from the default value 85 μM; for increased GSX inhibition, Ki was lowered to 8.5 μM. Deregulation and de-dimerization of MRP were similarly implemented as above for other enzymes.(D) Effects of alteration in GSH levels via gene disruption or GCL activity inhibition. Genetic disruption of Gclc and Gclm genes was implemented by either setting the respective genes to half of the default values for heterozygous deficiency or to zero for homozygous deficiency. GCL activity inhibition was implemented by lowering kc in Reaction 54 to 2.5% of the default value.
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pcbi-0030024-g012: Dose Response Curves of Electrophile X versus Stressor under Various Disrupted Conditions(A) Effects of deregulation of Gclc, Gclm, Gs, and Gst genes by Nrf2. Deregulation was implemented by clamping mRNAs of respective genes at levels seen at the basal condition.(B) Effects of lack of Nrf2 autoregulation and/or GST functioning as a homodimer. Removal of Nrf2 autoregulation was implemented similarly as in (A); de-dimerization of GST was implemented by replacing the quadratic term in Reaction 44 with a linear term that left GST concentration at the basal condition unchanged.(C) Effects of product inhibition of GST-catalyzed reaction. For reduced GSX inhibition, Ki in Reaction 57 was increased to 850 μM from the default value 85 μM; for increased GSX inhibition, Ki was lowered to 8.5 μM. Deregulation and de-dimerization of MRP were similarly implemented as above for other enzymes.(D) Effects of alteration in GSH levels via gene disruption or GCL activity inhibition. Genetic disruption of Gclc and Gclm genes was implemented by either setting the respective genes to half of the default values for heterozygous deficiency or to zero for homozygous deficiency. GCL activity inhibition was implemented by lowering kc in Reaction 54 to 2.5% of the default value.

Mentions: According to the two-gene control system analyzed in Text S5, inclusion of each additional feedback gene regulation adds to the loop gain (Equation S8). To examine the role of each individual gene regulation in the controllability of electrophile X, simulations were performed by clamping their expression levels at values seen at the basal condition. The results revealed that deregulation of genes responsible for GSH synthesis, i.e., Gclc, Gclm, and Gs, does not affect the controllability at low stressor levels significantly, as X level follows very closely that in the complete system (Figure 12A). However, the response diverges at intermediate stressor levels, swinging upward sharply with clamped Gs expression, but more mildly with clamped Gclc or Gclm expression. Regardless, the general superlinear-to-sublinear dose response profile seems to hold in these cases. In contrast, deregulation of Gst results in a sharp early rise in X level such that it enters the catastrophic phase at very low doses (Figure 12A, red line). Clamping Mrp gene expression resulted in an initial superlinear response that overlaps with that for the complete system, but it soon shoots upward almost vertically as the dose increases further (Figure 12C, red line). In summary, it appears that to keep the electrophile level contained, it is more crucial to adaptively upregulate Gst and Mrp than to enhance GSH replenishment by upregulating Gcl and Gs. Moreover, the simulation supports the concept that transcriptional feedback regulation of multiple anti-stress enzymes enhances the loop gain and improves the resistance to cellular stressors, albeit each individual gene regulation may exert its effect at different dose levels.


Dose response relationship in anti-stress gene regulatory networks.

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

Dose Response Curves of Electrophile X versus Stressor under Various Disrupted Conditions(A) Effects of deregulation of Gclc, Gclm, Gs, and Gst genes by Nrf2. Deregulation was implemented by clamping mRNAs of respective genes at levels seen at the basal condition.(B) Effects of lack of Nrf2 autoregulation and/or GST functioning as a homodimer. Removal of Nrf2 autoregulation was implemented similarly as in (A); de-dimerization of GST was implemented by replacing the quadratic term in Reaction 44 with a linear term that left GST concentration at the basal condition unchanged.(C) Effects of product inhibition of GST-catalyzed reaction. For reduced GSX inhibition, Ki in Reaction 57 was increased to 850 μM from the default value 85 μM; for increased GSX inhibition, Ki was lowered to 8.5 μM. Deregulation and de-dimerization of MRP were similarly implemented as above for other enzymes.(D) Effects of alteration in GSH levels via gene disruption or GCL activity inhibition. Genetic disruption of Gclc and Gclm genes was implemented by either setting the respective genes to half of the default values for heterozygous deficiency or to zero for homozygous deficiency. GCL activity inhibition was implemented by lowering kc in Reaction 54 to 2.5% of the default value.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0030024-g012: Dose Response Curves of Electrophile X versus Stressor under Various Disrupted Conditions(A) Effects of deregulation of Gclc, Gclm, Gs, and Gst genes by Nrf2. Deregulation was implemented by clamping mRNAs of respective genes at levels seen at the basal condition.(B) Effects of lack of Nrf2 autoregulation and/or GST functioning as a homodimer. Removal of Nrf2 autoregulation was implemented similarly as in (A); de-dimerization of GST was implemented by replacing the quadratic term in Reaction 44 with a linear term that left GST concentration at the basal condition unchanged.(C) Effects of product inhibition of GST-catalyzed reaction. For reduced GSX inhibition, Ki in Reaction 57 was increased to 850 μM from the default value 85 μM; for increased GSX inhibition, Ki was lowered to 8.5 μM. Deregulation and de-dimerization of MRP were similarly implemented as above for other enzymes.(D) Effects of alteration in GSH levels via gene disruption or GCL activity inhibition. Genetic disruption of Gclc and Gclm genes was implemented by either setting the respective genes to half of the default values for heterozygous deficiency or to zero for homozygous deficiency. GCL activity inhibition was implemented by lowering kc in Reaction 54 to 2.5% of the default value.
Mentions: According to the two-gene control system analyzed in Text S5, inclusion of each additional feedback gene regulation adds to the loop gain (Equation S8). To examine the role of each individual gene regulation in the controllability of electrophile X, simulations were performed by clamping their expression levels at values seen at the basal condition. The results revealed that deregulation of genes responsible for GSH synthesis, i.e., Gclc, Gclm, and Gs, does not affect the controllability at low stressor levels significantly, as X level follows very closely that in the complete system (Figure 12A). However, the response diverges at intermediate stressor levels, swinging upward sharply with clamped Gs expression, but more mildly with clamped Gclc or Gclm expression. Regardless, the general superlinear-to-sublinear dose response profile seems to hold in these cases. In contrast, deregulation of Gst results in a sharp early rise in X level such that it enters the catastrophic phase at very low doses (Figure 12A, red line). Clamping Mrp gene expression resulted in an initial superlinear response that overlaps with that for the complete system, but it soon shoots upward almost vertically as the dose increases further (Figure 12C, red line). In summary, it appears that to keep the electrophile level contained, it is more crucial to adaptively upregulate Gst and Mrp than to enhance GSH replenishment by upregulating Gcl and Gs. Moreover, the simulation supports the concept that transcriptional feedback regulation of multiple anti-stress enzymes enhances the loop gain and improves the resistance to cellular stressors, albeit each individual gene regulation may exert its effect at different dose 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