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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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Variation of Saturation Terms Affects the Length of Superlinear Controlled and Linear Uncontrolled Phases(A) Lowering the dissociation constant Kd for transcription factor T binding to the gene promoter shortens the superlinear highly controlled phase.(B) Lowering the Michaelis–Menten constant Km of enzyme G for clearance of Y shortens the linear uncontrolled phase.
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pcbi-0030024-g008: Variation of Saturation Terms Affects the Length of Superlinear Controlled and Linear Uncontrolled Phases(A) Lowering the dissociation constant Kd for transcription factor T binding to the gene promoter shortens the superlinear highly controlled phase.(B) Lowering the Michaelis–Menten constant Km of enzyme G for clearance of Y shortens the linear uncontrolled phase.

Mentions: Although in theory the Y versus S dose response curve could consist of at least four phases, the actual occurrence and length of each phase depends on whether the required individual gain-changing events exist and how far they are separated from each other in terms of level of S. If little or no basal constitutive activation exists, the initial superlinear phase will be minimal. The span of the superlinear second phase depends on how soon the signaling events leading to gene activation saturate. Advancing the gene saturation event by, for instance, lowering the Kd value for transcription factor T binding to the gene promoter, shortens the second phase (Figure 8A). The span of the linear third phase depends on the distance of separation between saturation of gene activation and that of clearance of Y by enzyme G. Simulation results indicated that with smaller Km for G, which brings the latter gain-changing event closer to the former, the linear phase increasingly shortens, and eventually plays little role in the overall shape of the curve (Figure 8B).


Dose response relationship in anti-stress gene regulatory networks.

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

Variation of Saturation Terms Affects the Length of Superlinear Controlled and Linear Uncontrolled Phases(A) Lowering the dissociation constant Kd for transcription factor T binding to the gene promoter shortens the superlinear highly controlled phase.(B) Lowering the Michaelis–Menten constant Km of enzyme G for clearance of Y shortens the linear uncontrolled phase.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0030024-g008: Variation of Saturation Terms Affects the Length of Superlinear Controlled and Linear Uncontrolled Phases(A) Lowering the dissociation constant Kd for transcription factor T binding to the gene promoter shortens the superlinear highly controlled phase.(B) Lowering the Michaelis–Menten constant Km of enzyme G for clearance of Y shortens the linear uncontrolled phase.
Mentions: Although in theory the Y versus S dose response curve could consist of at least four phases, the actual occurrence and length of each phase depends on whether the required individual gain-changing events exist and how far they are separated from each other in terms of level of S. If little or no basal constitutive activation exists, the initial superlinear phase will be minimal. The span of the superlinear second phase depends on how soon the signaling events leading to gene activation saturate. Advancing the gene saturation event by, for instance, lowering the Kd value for transcription factor T binding to the gene promoter, shortens the second phase (Figure 8A). The span of the linear third phase depends on the distance of separation between saturation of gene activation and that of clearance of Y by enzyme G. Simulation results indicated that with smaller Km for G, which brings the latter gain-changing event closer to the former, the linear phase increasingly shortens, and eventually plays little role in the overall shape of the curve (Figure 8B).

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