A systems- and signal-oriented approach to intracellular dynamics

2005 ◽  
Vol 33 (3) ◽  
pp. 507-515 ◽  
Author(s):  
O. Wolkenhauer ◽  
S.N. Sreenath ◽  
P. Wellstead ◽  
M. Ullah ◽  
K.-H. Cho
Keyword(s):  
Systems Biology ◽  
Dynamic Models ◽  
Cell Signalling ◽  
Science Research ◽  
Predictive Modelling ◽  
Mitogen Activated Protein Kinase ◽  
Simulation Studies ◽  
Simulated Environment ◽  
Mitogen Activated Protein ◽  
Modelling Simulation

A mathematical understanding of regulation, and, in particular, the role of feedback, has been central to the advance of the physical sciences and technology. In this article, the framework provided by systems biology is used to argue that the same can be true for molecular biology. In particular, and using basic modular methods of mathematical modelling which are standard in control theory, a set of dynamic models is developed for some illustrative cell signalling processes. These models, supported by recent experimental evidence, are used to argue that a control theoretical approach to the mechanisms of feedback in intracellular signalling is central to furthering our understanding of molecular communication. As a specific example, a MAPK (mitogen-activated protein kinase) signalling pathway is used to show how potential feedback mechanisms in the signalling process can be investigated in a simulated environment. Such ‘what if’ modelling/simulation studies have been an integral part of physical science research for many years. Using tools of control systems analysis, as embodied in the disciplines of systems biology, similar predictive modelling/simulation studies are now bearing fruit in cell signalling research.

scholarly journals Modular assembly of dynamic models in systems biology

2021 ◽  
Author(s):  
Michael Pan ◽  
Peter J. Gawthrop ◽  
Joseph Cursons ◽  
Edmund Crampin
Keyword(s):  
Systems Biology ◽  
Large Scale ◽  
Dynamic Models ◽  
Mitogen Activated Protein Kinase ◽  
Bond Graphs ◽  
Modular Assembly ◽  
Scale Models ◽  
Mitogen Activated Protein ◽  
Recent Developments ◽  
Modular Modelling

It is widely acknowledged that the construction of large-scale dynamic models in systems biology requires complex modelling problems to be broken up into more manageable pieces. To this end, both modelling and software frameworks are required to enable modular modelling. While there has been consistent progress in the development of software tools to enhance model reusability, there has been a relative lack of consideration for how underlying biophysical principles can be applied to this space. Bond graphs combine the aspects of both modularity and physics-based modelling. In this paper, we argue that bond graphs are compatible with recent developments in modularity and abstraction in systems biology, and are thus a desirable framework for constructing large-scale models. We use two examples to illustrate the utility of bond graphs in this context: a model of a mitogen-activated protein kinase (MAPK) cascade to illustrate the reusability of modules and a model of glycolysis to illustrate the ability to modify the model granularity.

scholarly journals Modular assembly of dynamic models in systems biology

2021 ◽  
Vol 17 (10) ◽  
pp. e1009513
Author(s):  
Michael Pan ◽  
Peter J. Gawthrop ◽  
Joseph Cursons ◽  
Edmund J. Crampin
Keyword(s):  
Systems Biology ◽  
Large Scale ◽  
Dynamic Models ◽  
Mitogen Activated Protein Kinase ◽  
Bond Graphs ◽  
Modular Assembly ◽  
Scale Models ◽  
Mitogen Activated Protein ◽  
Recent Developments ◽  
Modular Modelling

It is widely acknowledged that the construction of large-scale dynamic models in systems biology requires complex modelling problems to be broken up into more manageable pieces. To this end, both modelling and software frameworks are required to enable modular modelling. While there has been consistent progress in the development of software tools to enhance model reusability, there has been a relative lack of consideration for how underlying biophysical principles can be applied to this space. Bond graphs combine the aspects of both modularity and physics-based modelling. In this paper, we argue that bond graphs are compatible with recent developments in modularity and abstraction in systems biology, and are thus a desirable framework for constructing large-scale models. We use two examples to illustrate the utility of bond graphs in this context: a model of a mitogen-activated protein kinase (MAPK) cascade to illustrate the reusability of modules and a model of glycolysis to illustrate the ability to modify the model granularity.

Molecular targets of nitric-oxide-donating aspirin in cancer

2005 ◽  
Vol 33 (4) ◽  
pp. 701-704 ◽  
Author(s):  
K. Kashfi ◽  
B. Rigas
Keyword(s):  
Nitric Oxide ◽  
Cell Signalling ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Inhibition Of Proliferation ◽  
Mitogen Activated Protein ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

Nitric-oxide-donating aspirin (NO-ASA), consisting of ASA (aspirin) plus an -ONO2 moiety linked to it via a molecular spacer, is a new drug for cancer prevention. NO-ASA seems to overcome the low potency and toxicity of traditional ASA. The -ONO2 moiety is responsible for releasing NO, and it appears to be required for biological activity. In studies in vitro, NO-ASA inhibits the growth of colon, pancreatic, prostate, lung, skin, leukaemia and breast cancer cells, and is up to 6000-fold more potent than traditional ASA. This effect is owing to cell kinetics [inhibition of proliferation, induction of apoptosis (multiple criteria) and blocking the G1 to S cell-cycle transition] and cell signalling [inhibition of Wnt signalling (IC50=0.2 μM), inhibition of NF-κB (nuclear factor κB) activation (IC50=7.5 μM), inhibition of nitric oxide synthase-2 expression (IC50=48 μM), inhibition of MAPK (mitogen-activated protein kinase) signalling (IC50=10 μM) and induction of cyclo-oxygenase-2 at approx. 10 μM]. In studies in vivo, NO-ASA inhibits intestinal carcinogenesis in Min mice (tumour multiplicity was reduced by 59% after 3 weeks, with no effect in control animals and no side effects) and in the N-nitrosobis(2-oxopropyl)amine model of pancreatic cancer, where there was an 89% reduction in NO-ASA (3000 p.p.m. in the diet)-treated animals (P<0.001). There was no statistically significant effect by traditional ASA at equimolar doses. Our data indicate that NO-ASA is a highly promising agent for the prevention and/or treatment of cancer.

Modulation of signal-transduction pathways by chemopreventive agents

2000 ◽  
Vol 28 (2) ◽  
pp. 7-12 ◽  
Author(s):  
M. M. Manson ◽  
K. A. Holloway ◽  
L. M. Howells ◽  
E. A. Hudson ◽  
S. M. Plummer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Function ◽  
Cell Signalling ◽  
Growth Factor Receptor ◽  
Disease Process ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Chemopreventive Agents ◽  
Mitogen Activated Protein

For a disease such as cancer, where a number of alterations to normal cell function accumulate over time, there are several opportunities to inhibit, slow down or even reverse the process. Many of the changes which drive the disease process occur in cell-signalling pathways that regulate proliferation and apoptosis. As our knowledge of these complicated signalling networks improves, it is becoming clear that many molecules, both drugs and naturally occurring dietary constituents, can interact beneficially with deregulated pathways. Aspirin and other non-steroidal anti-inflammatory drugs, as well as natural compounds present in plants such as green vegetables and tea, can modulate signalling by affecting kinase activity and therefore phosphorylation of key molecules. Examples of pathways which can be modulated by these agents include activation of the transcription factor nuclear factor κB by tumour promoters or cytokines, signalling by growth factors through the growth-factor receptor/extracellular-regulated protein kinase pathways and by a number of other molecules through the stress-activated c-Jun N-terminal kinase and p38 pathways. These mitogen-activated protein kinase pathways regulate a number of transcription factors including c-Fos and c-Jun. Evidence exists, at least from in vitro experiments, that by targeting such pathways, certain dietary compounds may be able to restore abnormal rates of apoptosis and proliferation to more normal levels.

scholarly journals MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

2008 ◽  
Vol 115 (7) ◽  
pp. 203-218 ◽  
Author(s):  
Anthony J. Muslin
Keyword(s):  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Mapk Pathway ◽  
Science Research ◽  
Pharmacological Therapy ◽  
Model Systems ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

scholarly journals Lipid phosphate phosphohydrolase-1 degrades exogenous glycerolipid and sphingolipid phosphate esters

1999 ◽  
Vol 340 (3) ◽  
pp. 677-686 ◽  
Author(s):  
Renata JASINSKA ◽  
Qiu-Xia ZHANG ◽  
Carlos PILQUIL ◽  
Indrapal SINGH ◽  
James XU ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Cell Signalling ◽  
Mitogen Activated Protein Kinase ◽  
C Terminus ◽  
Liver Cdna Library ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphohydrolase ◽  
Ceramide 1

Lipid phosphate phosphohydrolase (LPP)-1 cDNA was cloned from a rat liver cDNA library. It codes for a 32-kDa protein that shares 87 and 82% amino acid sequence identities with putative products of murine and human LPP-1 cDNAs, respectively. Membrane fractions of rat2 fibroblasts that stably expressed mouse or rat LPP-1 exhibited 3.1-3.6-fold higher specific activities for phosphatidate dephosphorylation compared with vector controls. Increases in the dephosphorylation of lysophosphatidate, ceramide 1-phosphate, sphingosine 1-phosphate and diacylglycerol pyrophosphate were similar to those for phosphatidate. Rat2 fibroblasts expressing mouse LPP-1 cDNA showed 1.6-2.3-fold increases in the hydrolysis of exogenous lysophosphatidate, phosphatidate and ceramide 1-phosphate compared with vector control cells. Recombinant LPP-1 was located partially in plasma membranes with its C-terminus on the cytosolic surface. Lysophosphatidate dephosphorylation was inhibited by extracellular Ca2+ and this inhibition was diminished by extracellular Mg2+. Changing intracellular Ca2+ concentrations did not alter exogenous lysophosphatidate dephosphorylation significantly. Permeabilized fibroblasts showed relatively little latency for the dephosphorylation of exogenous lysophosphatidate. LPP-1 expression decreased the activation of mitogen-activated protein kinase and DNA synthesis by exogenous lysophosphatidate. The product of LPP-1 cDNA is concluded to act partly to degrade exogenous lysophosphatidate and thereby regulate its effects on cell signalling.

scholarly journals Inflammation in Diabetic Nephropathy

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Andy K. H. Lim ◽  
Gregory H. Tesch
Keyword(s):  
Diabetic Nephropathy ◽  
Cell Signalling ◽  
Inflammatory Cells ◽  
Mitogen Activated Protein Kinase ◽  
Amino Terminal ◽  
Human Diabetes ◽  
Mitogen Activated Protein ◽  
Experimental Approaches ◽  
End Stage

Diabetic nephropathy is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. This review examines the evidence for inflammation in the development and progression of diabetic nephropathy in both experimental and human diabetes, and provides an update on recent novel experimental approaches targeting inflammation and the lessons we have learned from these approaches. We highlight the important role of inflammatory cells in the kidney, particularly infiltrating macrophages, T-lymphocytes and the subpopulation of regulatory T cells. The possible link between immune deposition and diabetic nephropathy is explored, along with the recently described immune complexes of anti-oxidized low-density lipoproteins. We also briefly discuss some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines. Lastly, we present the latest data on the pathogenic role of the stress-activated protein kinases in diabetic nephropathy, from studies on the p38 mitogen activated protein kinase and the c-Jun amino terminal kinase cell signalling pathways. The genetic and pharmacological approaches which reduce inflammation in diabetic nephropathy have not only enhanced our understanding of the pathophysiology of the disease but shown promise as potential therapeutic strategies.

scholarly journals The myeloperoxidase-derived oxidant HOSCN inhibits protein tyrosine phosphatases and modulates cell signalling via the mitogen-activated protein kinase (MAPK) pathway in macrophages

2010 ◽  
Vol 430 (1) ◽  
pp. 161-169 ◽  
Author(s):  
Amanda E. Lane ◽  
Joanne T. M. Tan ◽  
Clare L. Hawkins ◽  
Alison K. Heather ◽  
Michael J. Davies
Keyword(s):  
Protein Kinase ◽  
Hypochlorous Acid ◽  
Mapk Pathway ◽  
Cell Signalling ◽  
Protein Tyrosine Phosphatases ◽  
Mitogen Activated Protein Kinase ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Protein Thiols ◽  
Mitogen Activated Protein

MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by hydrogen peroxide to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid) respectively. Specificity constants indicate that SCN− is a major substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. While HOCl and HOBr are powerful oxidizing agents, HOSCN is a less reactive, but more specific, oxidant which targets thiols and especially low pKa species. In the present study we show that HOSCN targets cysteine residues present in PTPs (protein tyrosine phosphatases) with this resulting in a loss of PTP activity for the isolated enzyme, in cell lysates and intact J774A.1 macrophage-like cells. Inhibition also occurs with MPO-generated HOCl and HOBr, but is more marked with MPO-generated HOSCN, particularly at longer incubation times. This inhibition is reversed by dithiothreitol, particularly at early time points, consistent with the reversible oxidation of the active site cysteine residue to give either a cysteine–SCN adduct or a sulfenic acid. Inhibition of PTP activity is associated with increased phosphorylation of p38a and ERK2 (extracellular-signal-regulated kinase 2) as detected by Western blot analysis and phosphoprotein arrays, and results in altered MAPK (mitogen-activated protein kinase) signalling. These data indicate that the highly selective targeting of some protein thiols by HOSCN can result in perturbation of cellular phosphorylation and altered cell signalling. These changes occur with (patho)physiological concentrations of SCN− ions, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage, particularly in smokers who have elevated plasma levels of SCN−.

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