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At least 397 records · Page 22Linked to original sources
PubMed2025

Multi-context modeling of driver pathways reveals common and specific mechanisms across 23 cancer types.

Discovery of cancer driver pathways is essential for targeted therapies, since these pathways govern tumor progression and treatment resistance. However, their context-specific patterns across populations remain poorly understood. Leveraging pan-cancer genomic data, we apply our two models, EntCDP and ModSDP, to perform stratified analyses from four perspectives: region, tumor type, age group, and risk factors. Our results reveal the regional biases in perturbed pathways, such as PI3K-Akt in Chinese patients and GPCR in American patients with bladder cancer. Subtype comparisons highlight the mTOR signaling in lung adenocarcinoma and the FoxO signaling in lung squamous cell carcinoma. Pediatric-adult comparisons emphasize the enrichment of Ras signaling in pediatric acute myeloid leukemia and PAK signaling in pediatric glioblastoma, respectively. Risk factor associations further link Notch-mediated pathways to alcohol consumption and CDKN-regulated pathways to obesity-related cancers. Our findings demonstrate the utility of stratified driver pathway analysis in uncovering common and specific mechanisms, which can help prioritize context-aware therapeutic targets.

Humans↗
PubMed2006

Hepatocyte growth factor differently influences Met-E-cadherin phosphorylation and downstream signaling pathway in two models of breast cells.

E-cadherins are implicated in cell adhesion, and also in cell signaling by associating with tyrosine kinase-receptors such as Met, the hepatocyte growth factor (HGF) receptor. Using two different cellular models, i.e. MCF-7 (breast carcinoma) and MCF-10 (immortalized mammary) cells, we studied the possible mechanism(s) by which E-cadherins modulate the signaling pathways downstream of Met, leading to beta-catenin-TCF transcriptional activity. In MCF-7, but not in MCF-10 cells, E-cadherins were remarkably associated with Met. Moreover, in MCF-7 cells both co-immunoprecipitation with anti-Met antibody and co-localization were increased by 30-min HGF treatment, which caused E-cadherin tyrosine phosphorylation. Also beta-catenin in the co-immunoprecipitate was phosphorylated by HGF, probably favoring TCF activation. Consistently, after HGF treatment, beta-catenin redistributed earlier in MCF-7 than in MCF-10 cells, with nuclear accumulation and activation of TOPFLASH gene reporter. Our results indicate a functional role of Met-E-cadherin interaction in MCF-7 cells through the amplification of the signaling downstream of HGF-Met triggering that involved c-Src and phosphoinositide-3-kinase activities.

Breast Neoplasms↗
PubMed2002

A quantitative model of human DNA base excision repair. I. Mechanistic insights.

Base excision repair (BER) is a multistep process involving the sequential activity of several proteins that cope with spontaneous and environmentally induced mutagenic and cytotoxic DNA damage. Quantitative kinetic data on single proteins of BER have been used here to develop a mathematical model of the BER pathway. This model was then employed to evaluate mechanistic issues and to determine the sensitivity of pathway throughput to altered enzyme kinetics. Notably, the model predicts considerably less pathway throughput than observed in experimental in vitro assays. This finding, in combination with the effects of pathway cooperativity on model throughput, supports the hypothesis of cooperation during abasic site repair and between the apurinic/apyrimidinic (AP) endonuclease, Ape1, and the 8-oxoguanine DNA glycosylase, Ogg1. The quantitative model also predicts that for 8-oxoguanine and hydrolytic AP site damage, short-patch Polbeta-mediated BER dominates, with minimal switching to the long-patch subpathway. Sensitivity analysis of the model indicates that the Polbeta-catalyzed reactions have the most control over pathway throughput, although other BER reactions contribute to pathway efficiency as well. The studies within represent a first step in a developing effort to create a predictive model for BER cellular capacity.

DNA Repair↗
PubMed1986

A computer model of neuronal pathways in the basal ganglia.

Disorders of the basal ganglia and the extrapyramidal motor system exhibit an imbalance of neurotransmitter concentrations in affected neurons. For three synapses with dopamine, acetylcholine, and gamma-amino butyric acid (GABA), mathematical models of synaptic transmission are developed. To describe the kinetics of transmitter substances, compartment analysis is used. Membrane potential behaviour is described by the Hodgkin-Huxley equations with an additional equation accounting for a presynaptic calcium current mediating transmitter release. At the postsynaptic site, activated receptor molecules control the activity of ion channels, eliciting either inhibitory or excitatory postsynaptic potentials. A simple model of the feedback loop connecting the caudate nucleus and the substantia nigra is simulated on a digital computer using the simulation language ACSL. A comparison of the control case with a model of Parkinson's disease shows a shift of eigenvalues towards zero in the diseased state.

Acetylcholine↗
PubMed1991

Ligand size as a determinant for catabolism by the low density lipoprotein (LDL) receptor pathway. A lattice model for LDL binding.

Low density lipoproteins (LDL) are large (Mr = 2.5 x 10(6)) in comparison to LDL receptors (Mr = 115,000). Since most LDL receptors are clustered in coated pits, we tested the hypothesis that crowding of receptor-bound LDL particles would cause steric effects. The apparent affinity of LDL for receptors on cultured fibroblasts decreased near saturation causing concave-upward Scatchard plots. Both the higher and lower affinity components of binding were up-regulated by the cholesterol synthesis inhibitor, lovastatin, indicating that the entire binding curve was sterol-responsive. In contrast, neither component of LDL binding was present on lovastatin-treated or untreated null fibroblasts which are incapable of expressing LDL receptors. Therefore, the concave-upward Scatchard plots were entirely due to binding to LDL receptors. These results are consistent with a lattice model in which receptor-bound LDL are large enough to decrease binding to adjacent receptors. A lattice model implies that large LDL should produce steric effects at a lower receptor occupancy than should small LDL. This was tested using seven LDL fractions that differed in diameter from 20 to 27 nm. Fewer large than small LDL were bound to the cell surface at 4 degrees C and 37 degrees C, and fewer were internalized and degraded at 37 degrees C. Since large LDL bound via both apolipoprotein (apo) E and apoB100, receptor cross-linking could have caused fewer large LDL to be bound at saturation. However, when the potential for cross-linking was prevented by an apo-E-specific monoclonal antibody (1D7), the difference in binding by large versus small LDL was not eliminated; instead, it was exaggerated. Taken together, these results support a lattice model for LDL binding and indicate that steric hindrance associated with crowding of LDL particles on receptor lattices is a major determinant for catabolism by the LDL receptor pathway in vitro.

Adult↗
PubMed2001

Modelling the vector pathway and infection of humans in an environmental outbreak of Escherichia coli O157.

Quantifying the transfer of Escherichia coli O157 from the environment to humans is essential for understanding outbreaks, establishing the infectious dose of the organism and proposing safeguards. We modelled the pathogen loading shed onto a field by sheep immediately prior to a scout camp where 18 scouts and two adults were infected with E. coli O157. We estimated the dose ingested (4-24 organisms) which is in agreement with the low infective dose reported previously for this organism in food outbreaks. These data closely fit a surrogate Shigella dose-response model which can be used as a basis for risk assessment.

Animals↗
PubMed2003

Drosophila mutants of the kynurenine pathway as a model for ageing studies.

A search for Drosophila mutants with phenotypes similar to human diseases might help to unravel evolutionary conserved genes implicated in polygenic human disorders. Among these are neurodegenerative diseases, characterized by a late onset disturbance of memory, structural brain impairments and altered content of the intermediates of the kynurenine pathway. The ratio between kynurenate (KYNA) and 3-hydroxykynurenine (3-HOK) in the brain is a critical determinant of neuronal viability. Therefore, the Drosophila mutants cinnabar (KYNA excess) and cardinal (3-HOK excess) allow an evaluation of the specific roles of these metabolites which present in physiologic concentrations and mimic systemic administration. Previously we have demonstrated that the mutant cardinal can serve as a model for dementia and can help to unravel the earliest manifestations of brain dysfunction. Here we show that a state of the brain control of locomotor coordination characterized by the parameters of sound production in males results from the neuroprotective and neurotoxic effects of KYNA and 3-HOK accumulated in young and aged Drosophila mutants. The high instability of 1) cycle form and number in pulses; 2) of pulse amplitude and 3) rhythm in the courtship song of aged cardinal males are similar to the alterations in mutants with defective central complex of the brain. The cardinal mutants demonstrate apoptosis in the brain after stress treatment. This might reflect the misbalance in the content of excitatory amino acids' and the glycine site agonists revealed by HPLC-determination. The mutant cinnabar proved to be normal in respect of the parameters studied.

Aging↗
PubMed1989

Cybernetic model of psychophysiologic pathways: II. Consciousness of tension and kinesthesia.

This paper describes a series of experiments directed toward the following questions: a) do signals from musculotendinous receptors reach consciousness?, and b) does feed-forward information of muscular force and expected extent of voluntary movement exist? To answer these questions, data from voluntary compression of springs and strain-gauge have been analyzed in healthy young subjects. By successive elimination of information from other sources, it was possible to verify that receptors in muscles and tendons do signal movement magnitude and muscular tension to the cerebral cortex, and that this information does reach consciousness. There also exists a feed-forward mechanism signalling parameters of voluntary contraction. However, it is unclear whether peripheral, subcortical or intracortical loops are directly involved.

Biofeedback, Psychology↗
PubMed2002

Copper-dependent iron assimilation pathway in the model photosynthetic eukaryote Chlamydomonas reinhardtii.

The unicellular green alga Chlamydomonas reinhardtii is a valuable model for studying metal metabolism in a photosynthetic background. A search of the Chlamydomonas expressed sequence tag database led to the identification of several components that form a copper-dependent iron assimilation pathway related to the high-affinity iron uptake pathway defined originally for Saccharomyces cerevisiae. They include a multicopper ferroxidase (encoded by Fox1), an iron permease (encoded by Ftr1), a copper chaperone (encoded byAtx1), and a copper-transporting ATPase. A cDNA, Fer1, encoding ferritin for iron storage also was identified. Expression analysis demonstrated that Fox1 and Ftrl were coordinately induced by iron deficiency, as were Atx1 and Fer1, although to lesser extents. In addition, Fox1 abundance was regulated at the posttranscriptional level by copper availability. Each component exhibited sequence relationship with its yeast, mammalian, or plant counterparts to various degrees; Atx1 of C. reinhardtii is also functionally related with respect to copper chaperone and antioxidant activities. Fox1 is most highly related to the mammalian homologues hephaestin and ceruloplasmin; its occurrence and pattern of expression in Chlamydomonas indicate, for the first time, a role for copper in iron assimilation in a photosynthetic species. Nevertheless, growth of C. reinhardtii under copper- and iron-limiting conditions showed that, unlike the situation in yeast and mammals, where copper deficiency results in a secondary iron deficiency, copper-deficient Chlamydomonas cells do not exhibit symptoms of iron deficiency. We propose the existence of a copper-independent iron assimilation pathway in this organism.

Adenosine Triphosphatases↗
PubMed2005

Intramolecular signaling pathways revealed by modeling anisotropic thermal diffusion.

A variety of experimental evidence suggests that rapid, long-range propagation of conformational changes through the core of proteins plays a vital role in allosteric communication. Here, we describe a non-equilibrium molecular dynamics simulation method, anisotropic thermal diffusion (ATD), which allowed us to observe a dominant intramolecular signaling pathway in PSD-95, a member of the PDZ domain protein family. The observed pathway is in good accordance with a pathway previously inferred using a multiple sequence analysis of 276 PDZ domain proteins. In comparison with conventional solution molecular dynamics methods, the ATD method provides greatly enhanced signal-to-noise, allowing long-distance correlations to be observed clearly. The ATD method requires neither a large number of homologous proteins, nor extremely long simulation times to obtain a complete signaling pathway within a protein. Therefore, the ATD method should prove to be a powerful and general complement to experimental efforts to understand the physical basis of intramolecular signaling.

Allosteric Site↗
PubMed2006

Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder.

BACKGROUND: Despite extensive research, the molecular/cellular underpinnings of bipolar disorder (BD) remain to be fully elucidated. Recent data has demonstrated that mood stabilizers exert major effects on signaling that regulate cellular plasticity; however, a direct extrapolation to mechanisms of disease demands proof that manipulation of candidate genes, proteins, or pathways result in relevant behavioral changes. METHODS: We critique and evaluate the behavioral changes induced by manipulation of cellular plasticity cascades implicated in BD. RESULTS: Not surprisingly, the behavioral data suggest that several important signaling molecules might play important roles in mediating facets of the complex symptomatology of BD. Notably, the protein kinase C and extracellular signal-regulated kinase cascades might play important roles in the antimanic effects of mood stabilizers, whereas glycogen synthase kinase (GSK)-3 might mediate facets of lithium's antimanic/antidepressant actions. Glucocorticoid receptor (GR) modulation also seems to be capable to inducing affective-like changes observed in mood disorders. And Bcl-2, amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, and inositol homeostasis represent important pharmacological targets for mood stabilizers, but additional behavioral research is needed to more fully delineate their behavioral effects. CONCLUSIONS: Behavioral data support the notion that regulation of cellular plasticity is involved in affective-like behavioral changes observed in BD. These findings are leading to the development of novel therapeutics for this devastating illness.

Animals↗
PubMed1999

Mathematical models of metabolic pathways.

There have been recent advances in metabolic flux analysis. In particular, the marriage of traditional flux balancing with NMR isotopomer distribution analysis holds great promise for the detailed quantification of physiology. Nevertheless, flux analysis yields only static snap-shots of metabolism. To robustly predict the time evolution of metabolic networks, dynamic mathematical models, especially those that contain a description of both gene expression as well as enzyme activity, must be utilized. When mechanistic control and regulatory information is not available, heuristic-based methods, such as the cybernetic framework, can be employed to describe the action of these control mechanisms. In the 'high-information' future, as more biological information becomes available, such heuristic-based approaches can be replaced by mechanistic mass-action representations of physiology that stem directly from genetic sequence.

Animals↗
PubMed2005

Modeling and simulation in signal transduction pathways: a systems biology approach.

Modeling, the heart of systems biology, of complex processes (example: signal transduction) is a wide scientific discipline where many approaches from different areas are confronted with the aim of better understanding, identifying and modeling of complex data coming from various sources. The purpose of this paper is to introduce the basic steps of systems biology view towards signaling pathways, which mainly deals with the computational tools. The paper emphasizes the modeling and simulation approach in the signal transduction pathways using the topologies of the biochemical reactions with an overview of the different types of software platforms. Finally, we demonstrated the epidermal growth factor receptor signaling pathway model as an example to study the growth factor mediated signaling system with biological experiments. This paper will enables new comers to underline the strengths of the computational approaches towards signal transduction, as well as to highlight the systems biology research directions.

Animals↗
PubMed1989

Cybernetic model of psychophysiologic pathways: III. Clinical impairment of tension and kinesthesia.

It is unclear whether peripheral, subcortical or intracortical loops are directly involved between receptors in muscles and tendons and the cerebral cortex in signaling movement magnitude and muscular tension information. Previous experiments have indicated that this information does reach consciousness. Data from voluntary compression of springs and strain-gauge were analyzed in patients with unilateral focal lesions of the cerebral hemispheres. It was found that the perception of signals of muscular tension is abolished by lesions of the contralateral cortex near the central sulcus. It was concluded that the possibility exists of separate cortical projection areas for kinesthetic signals from muscles and from joints.

Brain Diseases↗
PubMed1998

Equilibrium unfolding (folding) pathway of a model H-type pseudoknotted RNA: the role of magnesium ions in stability.

In T2 and related T-even bacteriophages, the upstream autoregulatory mRNA leader sequence of gene 32 folds into a simple tertiary structural motif, a hairpin (H)-type pseudoknot. This pseudoknot is derived from 32 contiguous nucleotides which form two coaxially stacked helical stems that adopt a pseudocontinuous A-form helical structure. These stems are connected by two nonequivalent single-stranded loops. The equilibrium unfolding pathway of a 36-nucleotide RNA fragment corresponding to the wild-type and sequence variants of the T2 gene 32 mRNA pseudoknot has been probed as a function of [Mg2+] by analysis of dual optical wavelength, equilibrium thermal melting profiles. A van't Hoff model based on multiple sequential, two-state unfolding transitions has been applied to the resultant data. Compensatory base pair substitutions incorporated into the helical stems have been used to assign optical melting transitions to molecular unfolding events. The optical melting profile of the wild-type RNA is minimally described by three sequential unfolding transitions. The helix-helix junction region melts first in a low-enthalpy transition, followed by the unfolding of the remainder of helical stem 2, and then, all of stem 1. The total enthalpy of unfolding (folding) at [Mg2+] >/= 1 mM is accounted for by the secondary structure alone, suggesting that, if any non-Watson-Crick or tertiary structure exists in this conformation, it makes little or no enthalpic contribution to the stability of the molecule. Consistent with this, the [Mg2+] dependence of individual unfolding transitions within the pseudoknot is well-described by differential extents of delocalized binding of Mg2+ to folded and unfolded regions of the molecule. At a fixed [Mg2+], the helix junction region and stem 2 sequester more Mg2+ ions than the stem 1 hairpin; a larger fraction of these ions are then released upon unfolding. Two base or base pair substitution mutant RNAs which destabilize the helical junction and/or the base of stem 2 appear to sequester fewer ions, with a correspondingly smaller number of these ions released upon unfolding.

Base Pairing↗
PubMed2001

Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint.

From an oncological and immunological perspective, the T-cell-mediated induction of psoriatic plaques should be prone to malignant transformation as the phenotype of psoriatic plaques includes: chronic inflammation, epidermal hyperplasia, prolonged survival and elevated telomerase levels in lesional keratinocytes, as well as angiogenesis, exposure to carcinogens and immunosuppressants. However, conversion of a psoriatic plaque to squamous cell carcinoma is exceedingly rare. This paper explores the possible molecular mechanism for the tumor suppressor pathway in psoriatic lesions, with an emphasis on a putative senescence-switch involving p16.

Carcinoma, Squamous Cell↗