2020 7th International Conference on Biomedical and Bioinformatics Engineering, 2020
Understanding how cell fate is determined when exposed to extreme stresses such as heat shock is ... more Understanding how cell fate is determined when exposed to extreme stresses such as heat shock is critical in biomedical systems. It has long been understood that exposure of cells to high temperature typically protect themselves with a heat shock response (HSR), where accumulation of denatured or unfolded proteins triggers the synthesis of heat shock proteins (HSPs) through the heat shock transcription factor, e.g., heat shock factor 1 (HSF1). Recent experimental work has also shown that protein posttranslational modifications (PTMs) such as SUMOylation play crucial roles in cellular responses to heat shock. As a complementary approach to the current experimental methodologies, in this study we aim to develop a mathematical model of SUMOylation-development synergism of HSR for the purpose of studying the dynamical behaviour of HSR quantitatively. The structure of our dynamical model is derived mostly from mass action kinetics while the model parameters are optimized by using a genetic algorithm (GA) based data-driven approach. The preliminary results show GA based data-driven approach has potentials for our modelling purpose.
Dysregulation of the mitochondrial fission machinery has been linked to cell death following isch... more Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-xL, an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-xL interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-xL interaction. Our data suggest that Mff primes Drp1 binding to Bcl-xL at the mitochondria and that Mff and Bcl-xL can interact directly, independent of Drp1...
Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and patholog... more Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and pathological situations, such as ischemia and cancer. Recent experimental data have shown that protein post-translational modifications (PTMs), in particular SUMOylation, play crucial roles in cellular response to hypoxia. In this study, we develop a mathematical model of SUMOylation-dependent synergism of hypoxia response to gain a better understanding of how HIF interacts with SUMO proteins to sense oxygen and respond to hypoxia. The primary result shows the effect of oxygen concentration on SUMO conjugation level. Clinical Relevance— This result has implications for cancer treatment by using model prediction to drug treatment under varying degrees of hypoxia.
Dysregulation of the mitochondrial fission machinery has been linked to cell death following isch... more Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-xL , an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-xL interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-xL interaction. Our data suggest that Mff primes Drp1 binding to Bcl-xL at the mitochondria and that Mff and Bcl-x L can interact directly, independent of Drp1, through their transmembrane domains. Importantly, SENP3 loss in cells subjected to OGD correlates with reduced Drp1-Bcl-xL interaction, whilst recovery of SENP3 levels in cells subjected to reoxygenation following OGD correlates with increased Drp1-Bcl-xL interaction. Expressing a Bcl-xL mutant with defective Drp1 binding reduces OGD plus reoxygenation-evoked cell death. Taken together, our results indicate that SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-xL interaction that contributes to cell death following ischemia.
Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and patholog... more Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and pathological situations, such as ischemia and cancer. Recent experimental data have shown that protein post-translational modifications (PTMs), in particular SUMOylation, play crucial roles in cellular response to hypoxia. In this study, we develop a mathematical model of SUMOylation-dependent synergism of hypoxia response to gain a better understanding of how HIF interacts with SUMO proteins to sense oxygen and respond to hypoxia. The primary result shows the effect of oxygen concentration on SUMO conjugation level. Clinical Relevance— This result has implications for cancer treatment by using model prediction to drug treatment under varying degrees of hypoxia.
2020 7th International Conference on Biomedical and Bioinformatics Engineering, 2020
Understanding how cell fate is determined when exposed to extreme stresses such as heat shock is ... more Understanding how cell fate is determined when exposed to extreme stresses such as heat shock is critical in biomedical systems. It has long been understood that exposure of cells to high temperature typically protect themselves with a heat shock response (HSR), where accumulation of denatured or unfolded proteins triggers the synthesis of heat shock proteins (HSPs) through the heat shock transcription factor, e.g., heat shock factor 1 (HSF1). Recent experimental work has also shown that protein posttranslational modifications (PTMs) such as SUMOylation play crucial roles in cellular responses to heat shock. As a complementary approach to the current experimental methodologies, in this study we aim to develop a mathematical model of SUMOylation-development synergism of HSR for the purpose of studying the dynamical behaviour of HSR quantitatively. The structure of our dynamical model is derived mostly from mass action kinetics while the model parameters are optimized by using a genetic algorithm (GA) based data-driven approach. The preliminary results show GA based data-driven approach has potentials for our modelling purpose.
Dysregulation of the mitochondrial fission machinery has been linked to cell death following isch... more Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-xL, an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-xL interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-xL interaction. Our data suggest that Mff primes Drp1 binding to Bcl-xL at the mitochondria and that Mff and Bcl-xL can interact directly, independent of Drp1...
Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and patholog... more Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and pathological situations, such as ischemia and cancer. Recent experimental data have shown that protein post-translational modifications (PTMs), in particular SUMOylation, play crucial roles in cellular response to hypoxia. In this study, we develop a mathematical model of SUMOylation-dependent synergism of hypoxia response to gain a better understanding of how HIF interacts with SUMO proteins to sense oxygen and respond to hypoxia. The primary result shows the effect of oxygen concentration on SUMO conjugation level. Clinical Relevance— This result has implications for cancer treatment by using model prediction to drug treatment under varying degrees of hypoxia.
Dysregulation of the mitochondrial fission machinery has been linked to cell death following isch... more Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-xL , an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-xL interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-xL interaction. Our data suggest that Mff primes Drp1 binding to Bcl-xL at the mitochondria and that Mff and Bcl-x L can interact directly, independent of Drp1, through their transmembrane domains. Importantly, SENP3 loss in cells subjected to OGD correlates with reduced Drp1-Bcl-xL interaction, whilst recovery of SENP3 levels in cells subjected to reoxygenation following OGD correlates with increased Drp1-Bcl-xL interaction. Expressing a Bcl-xL mutant with defective Drp1 binding reduces OGD plus reoxygenation-evoked cell death. Taken together, our results indicate that SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-xL interaction that contributes to cell death following ischemia.
Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and patholog... more Hypoxia, low oxygen level in tissues, is encountered in both physiological processes and pathological situations, such as ischemia and cancer. Recent experimental data have shown that protein post-translational modifications (PTMs), in particular SUMOylation, play crucial roles in cellular response to hypoxia. In this study, we develop a mathematical model of SUMOylation-dependent synergism of hypoxia response to gain a better understanding of how HIF interacts with SUMO proteins to sense oxygen and respond to hypoxia. The primary result shows the effect of oxygen concentration on SUMO conjugation level. Clinical Relevance— This result has implications for cancer treatment by using model prediction to drug treatment under varying degrees of hypoxia.
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Papers by Alice Zhao