Abstract:
:The investigation of the structure and dynamics of signal transduction systems through data-based mathematical models in ordinary differential equations or other paradigms has proven to be a successful approach in recent times. Extending this concept, we here analysed the use of kinetic models based on power-law terms with non-integer kinetic orders in the validation of hypotheses concerning regulatory structures in signalling systems. We integrated pre-existent biological knowledge, hypotheses and experimental quantitative data into a power-law model to validate the existence of certain regulatory loops in the Ras/Raf-1/MEK/ERK pathway, a MAPK pathway involved in the transduction of mitogenic and differentiation signals. Towards this end, samples of a human mammary epithelial cell line (MCF-10A) were used to obtain time-series data, characterising the behaviour of the system after epidermal growth factor stimulation in different scenarios of expression for the critical players of the system regarding the investigated loops (e.g., the inhibitory protein RKIP). The mathematical model was calibrated using a computational procedure that included: analysis of structural identifiability, global ranking of parameters to detect the most sensitivity ones towards the experimental setup, model calibration using global optimization methods to find the parameter values that better fit the data, and practical identifiability analysis to estimate the confidence in the estimated values for the parameters. The obtained model was used to perform computational simulations concerning the role of the investigated regulatory loops in the time response of the signalling pathway. Our findings suggest that the special regularity in the structure of the power-law terms make them suitable for a data-based validation of regulatory loops in signalling pathways. The model-based analysis performed identified RKIP as an actual inhibitor of the activation of the ERK pathway, but also suggested the existence of an intense feedback-loop control of the pathway by the activated ERK that maybe responsible for the damped oscillations we saw in the fraction of activated MEK both in the experiments and simulations. In addition, the model analysis suggested that phosphorylation/deactivation of RKIP during the transient stimulation may have a significant effect on the signalling peaks of both MEK and ERK. This later result suggests that dynamic modulation of signal inhibitors during stimulation may be a regulatory mechanism in ERK signalling and other pathways.
journal_name
Mol Biosystjournal_title
Molecular bioSystemsauthors
Vera J,Rath O,Balsa-Canto E,Banga JR,Kolch W,Wolkenhauer Odoi
10.1039/c0mb00018csubject
Has Abstractpub_date
2010-11-01 00:00:00pages
2174-91issue
11eissn
1742-206Xissn
1742-2051journal_volume
6pub_type
杂志文章abstract::There are major issues regarding the proposed pathway for starch degradation in germinating cereal grain. Given the commercial importance but genetic intractability of the problem, we have embarked on a program of chemical genetics studies to identify and dissect the pathway and regulation of starch degradation in ger...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c0mb00204f
更新日期:2011-03-01 00:00:00
abstract::The emerging field of synthetic biology is generating insatiable demands for synthetic genes, which far exceed existing gene synthesis capabilities. This review discusses the current methods of chemical DNA synthesis and gene assembly, as well as the latest engineering tools, technologies and trends which could potent...
journal_title:Molecular bioSystems
pub_type: 杂志文章,评审
doi:10.1039/b822268c
更新日期:2009-07-01 00:00:00
abstract::Within systems biology there is an increasing interest in the stochastic behavior of genetic and biochemical reaction networks. An appropriate stochastic description is provided by the chemical master equation, which represents a continuous time Markov chain (CTMC). In this paper we consider the stochastic properties ...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c1mb05086a
更新日期:2011-10-01 00:00:00
abstract::Upon entering biological systems, such as the blood stream, nanoparticles form molecular complexes with the proteins encountered called protein coronas, which shield the surface of the exogenous nanoparticle. The most abundant blood proteins, such as albumin, initially occupy the surface of the nanoparticle. Owing to ...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c4mb00591k
更新日期:2015-02-01 00:00:00
abstract::Osteosarcoma (OS) is a highly malignant bone tumour, affecting mainly children and young adults between 10 and 20 years of age. It represents the most frequent primitive malignant tumour of the skeletal system and is characterized by an extremely aggressive clinical course, with rapid development of lung metastases. I...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c3mb70328b
更新日期:2014-06-01 00:00:00
abstract::4-Aminoantipyrine (AAP) is scarcely administered as an analgesic drug because of the potential side effects. The residue of AAP in the environment possesses a potential threat to human health. In this article, the binding mode of AAP with the important antioxidant enzyme catalase (CAT) was investigated using spectrosc...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c1mb05271c
更新日期:2011-11-01 00:00:00
abstract::This paper describes a sensitive, non-destructive displacement assay, using a fluorescent peptide indicator, for real-time monitoring of the interactions between RNA and RNA binding proteins (RBPs). The developed fluorescent peptide indicators, each containing a mid-sequence fluorophore unit, allowed sensing of target...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c2mb25470k
更新日期:2013-05-01 00:00:00
abstract::The protein kinase C (PKC) family of serine/threonine kinases is an attractive drug target for the treatment of cancer and other diseases. Diacylglycerol (DAG), phorbol esters and others act as ligands for the C1 domain of PKC isoforms. Inspection of the crystal structure of the PKCδ C1b subdomain in complex with phor...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c2mb05452c
更新日期:2012-04-01 00:00:00
abstract::Undoubtedly, metabonomics can reveal the comprehensive efficacies of traditional Chinese medicine (TCM) formulae and its complex mechanism at the molecular biological level. In this study, an attempt was made to address the pretreatment effect of a TCM formula. In this case, as a critical point, we should first know h...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c4mb00529e
更新日期:2015-02-01 00:00:00
abstract::The underlying reasons for the differences in the virulence of various types of Ebola virus (EBOV) remain unknown. Comparison of the percentage of disorder (PID) in nucleocapsid proteins VP30 and NP reveals high correlation between nucleocapsid PIDs and the case-fatality rates of EBOV. The higher disorder of these pro...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c5mb00240k
更新日期:2015-08-01 00:00:00
abstract::Human mitogen-activated protein kinase (MAPK) family members JNK and p38 are two homologous protein-serine/threonine kinases but play distinct roles in the pathological process of neurological disorders. Selective targeting of JNK over p38 has been established as a potential therapeutic approach to epilepsy and other ...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c6mb00297h
更新日期:2016-07-19 00:00:00
abstract::Single molecule observation of fluorescence resonance energy transfer can be used to provide insight into the structure and dynamics of proteins. Using a straightforward triple-colour labelling strategy, we present a measurement and analysis scheme that can simultaneously study multiple regions within single intrinsic...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c2mb25135c
更新日期:2012-10-01 00:00:00
abstract::Cell penetrating peptides (CPPs), TATp, in particular, has been used widely for intracellular delivery of various agents ranging from small molecules to proteins, peptides, range of pharmaceutical nanocarriers and imaging agents. This review highlights the mechanisms of CPP-mediated delivery and summarizes numerous ex...
journal_title:Molecular bioSystems
pub_type: 杂志文章,评审
doi:10.1039/b916297f
更新日期:2010-04-01 00:00:00
abstract::The major mechanical function of talin is to couple the β-integrin cytoplasmic tails to actin filaments. A variety of β-integrin tails contain conserved binding motifs for talin, and recent research shows that β-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While ta...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c4mb00341a
更新日期:2014-12-01 00:00:00
abstract::Despite many prior studies on microbial response to oxidative stress, our understanding of microbial tolerance against oxidative stress is currently limited to aerobic conditions, and few engineering strategies have been devised to resolve toxicity issues of oxidative stress under anaerobic conditions. Since biologica...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c2mb25259g
更新日期:2013-02-02 00:00:00
abstract::Migraine is a common brain disorder characterized by recurrent attacks of severe headaches and other neurological symptoms. In one-third of patients headaches are accompanied by auras, which consist of transient visual and sensory disturbances, believed to be caused by cortical spreading depression (CSD). CSD is chara...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c5mb00049a
更新日期:2015-05-01 00:00:00
abstract::Gene regulatory networks constitute the first layer of the cellular computation for cell adaptation and surveillance. In these webs, a set of causal relations is built up from thousands of interactions between transcription factors and their target genes. The large size of these webs and their entangled nature make it...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/B904960f
更新日期:2009-12-01 00:00:00
abstract::The ectonucleotide phosphodiesterase/pyrophosphatase-1 (NPP1) is a type II transmembrane glycoprotein that regulates extracellular inorganic purine nucleotide and inorganic diphosphate levels through the hydrolysis of ATP into AMP and diphosphate. NPP1 is a promising drug target as it plays a role in several disorders...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c7mb00095b
更新日期:2017-05-30 00:00:00
abstract::Escherichia coli has evolved an intracellular pathway to regulate its motion termed as chemotaxis so as to move towards a favorable environment such as regions with higher concentration of nutrients. Chemotaxis is a response to temporal and spatial variation of extracellular ligand concentration and randomness in moti...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/b924368b
更新日期:2010-06-01 00:00:00
abstract::As one of the most important trace elements within an organism, zinc has been shown to be involved in numerous biological processes and closely implicated in various diseases. The zinc ion is important for proteins to perform their functional roles. To provide in-depth functional annotation of zinc-binding proteins, a...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c3mb70100j
更新日期:2013-09-01 00:00:00
abstract::Drug promiscuity is one of the key issues in current drug development. Many famous drugs have turned out to behave unexpectedly due to their propensity to bind to multiple targets. One of the primary reasons for this promiscuity is that drugs bind to multiple distinctive target environments, a feature that we call mul...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/b901356c
更新日期:2009-08-01 00:00:00
abstract::Complex signalling systems have evolved in multicellular organisms to enable cell-to-cell communication during growth and development. In plants, cell communication via the extracellular matrix (apoplast) controls many processes vital for plant survival. Secretion of ATP into the extracellular matrix is now recognised...
journal_title:Molecular bioSystems
pub_type: 杂志文章,评审
doi:10.1039/c1mb05278k
更新日期:2012-02-01 00:00:00
abstract::Comparative analysis of the complete genome sequences from a variety of poorly studied organisms aims at predicting ecological and behavioral properties of these organisms and helping in characterizing their habitats. This task requires finding appropriate descriptors that could be correlated with the core traits of e...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/b908047c
更新日期:2010-04-01 00:00:00
abstract::Infectious diseases caused by bacterial pathogens pose a major concern to public health and, thus, greater attention must be given to providing insightful knowledge on host-pathogen interactions. There are several theories addressing the dynamics of complex mechanisms of host-pathogen interactions. The availability of...
journal_title:Molecular bioSystems
pub_type: 杂志文章,评审
doi:10.1039/c7mb00372b
更新日期:2017-11-21 00:00:00
abstract::The dairy bacterium Lactococcus lactis has to master a complicated task. It must control its essentially linear glycolytic pathway in such a fashion that, when the substrate, glucose, runs out, it retains enough phosphoenolpyruvate and fructose-1,6-bisphosphate to be able to restart glycolysis as soon as new glucose b...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c5mb00726g
更新日期:2016-01-01 00:00:00
abstract::A growing number of diverse proteins are being identified that moonlight. Moonlighting proteins comprise an interesting subset of multifunctional proteins in which the two functions are found in a single polypeptide chain. They do not include proteins that are multifunctional due to gene fusions, families of homologou...
journal_title:Molecular bioSystems
pub_type: 杂志文章,评审
doi:10.1039/b900658n
更新日期:2009-04-01 00:00:00
abstract::A novel class of pH-sensitive PEG lipids bearing acid-cleavable acetal linkages and short PEG chains have been synthesised and used in ternary vector formulations. The cleavage pH was influenced by structural components including the terminal PEG moiety and spacer length. ...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/b719782a
更新日期:2008-06-01 00:00:00
abstract::All trans-retinoic acid (ATRA) is widely used to direct the differentiation of cultured stem cells. When exposed to the pluripotent human embryonal carcinoma (EC) stem cell line, TERA2.cl.SP12, ATRA induces ectoderm differentiation and the formation of neuronal cell types. We report in this study that novel polyene ch...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c3mb70273a
更新日期:2013-12-01 00:00:00
abstract::Abundant information about the nucleotide sequence of the human genome has become readily available and it is now necessary to develop methods for the identification of genes that are involved in important cellular, developmental and disease-related processes. Identification methods based on the activities of hammerhe...
journal_title:Molecular bioSystems
pub_type: 杂志文章,评审
doi:10.1039/b503235k
更新日期:2005-05-01 00:00:00
abstract::Understanding the molecular mechanism that underlies the differentiation of neural stem cells (NSCs) is vital to develop regenerative medicines for neurological disorders. In our previous work, Rho-GDI-γ was found to be able to prompt neuronal differentiation when it was down regulated. However, it is unclear how Rho-...
journal_title:Molecular bioSystems
pub_type: 杂志文章
doi:10.1039/c2mb25147g
更新日期:2012-11-01 00:00:00