Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,657 records · Page 92Linked to original sources
PubMed1991

Epicardial mapping in patients with "nodoventricular" accessory pathways.

Some patients with electrophysiologic features suggesting nodoventricular fibers have been shown to have right parietal atrioventricular (AV) accessory pathways with decremental conduction properties intraoperatively. The experience with 11 patients (7 women and 4 men, mean age +/- standard deviation 25 +/- 5 years) who had electrophysiologic features consistent with a nodoventricular pathway and who underwent operative correction was reviewed. At electrophysiologic study, all patients had absent or minimal preexcitation in sinus rhythm. During atrial pacing and extrastimulus testing, maximal preexcitation with left bundle branch block morphology developed and the AH and AV intervals progressively prolonged. Preexcited tachycardia was initiated in all patients (AV reentrant tachycardia in 10 patients and AV node reentrant tachycardia in 1 patient). At operation all patients had a right parietal accessory pathway demonstrated. Intraoperative mapping demonstrated the earliest site of ventricular activation during anterograde preexcitation to be at the midanterior right ventricle, consistent with insertion of these pathways into the right bundle branch system, in 7 patients. The ventricular insertion was at the AV groove in 4 patients, in keeping with the typical Wolff-Parkinson-White syndrome. Retrograde conduction over the pathway was not demonstrated in any patient. Two patients had evidence of a second accessory AV pathway in the left paraseptal region. Operative AV node ablation was electively performed in 2 patients without affecting preexcitation in either case. In 1 of these patients, accessory pathway conduction was temporarily abolished by ice mapping in the right anterolateral AV groove.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Radiofrequency ablation of accessory pathways associated with congenital heart disease including heterotaxy syndrome.

Congenital heart disease complicates the management of most accessory pathway-mediated tachycardias and also increases the challenge of radiofrequency ablation. Since 1990, radiofrequency ablation of accessory atrioventricular (AV) pathways has been attempted in 10 patients (age range 3.5 months to 30 years) with congenital heart disease: Ebstein's anomaly (n = 5), heterotaxy with AV discordance (n = 3), tetralogy of Fallot (n = 1) and total anomalous pulmonary venous return (n = 1). Eight patients had manifest Wolff-Parkinson-White syndrome and 2 had concealed pathways. Five patients had multiple pathways including 4 of the 5 with Ebstein's anomaly. Of 16 pathways total, 15 were associated with the tricuspid valve including all pathways in the patients with Ebstein's anomaly and heterotaxy. The His bundle area was identified in all patients and involved an anterior AV node in 2 of 3 with heterotaxy. Ablation was performed on the atrial side of the AV ring in all cases. No instance of AV block was encountered. Complete success was achieved in 6 patients including the 3 with heterotaxy. In 2 patients, manifest preexcitation was eliminated and clinical symptoms were greatly modified. The procedure was transiently successful in 1 patient who later had surgical interruption of the accessory pathway during tetralogy of Fallot repair. Ablation was unsuccessful in 1 patient. Thus, the overall success was 80%.

Adolescent↗
PubMed1994

Comparison of radiofrequency catheter ablation procedures in children, adolescents, and adults and the impact of accessory pathway location.

Radiofrequency (RF) catheter ablation is an accepted treatment for supraventricular tachycardia. However, the determinants of success, difficulty, or risk of complication associated with ablation have not been defined. This study evaluated patient age and location of the accessory or extranodal pathway as determinants of these procedural variables. Patients were stratified by age, with those aged 2 to 12 years classified as children, those aged 13 to 19 years as adolescents, and those > or = 20 years as adults. Locations were defined as right, septal, or left free wall accessory pathways, or extranodal slow pathways associated with atrioventricular node reentrant tachycardia. A total of 443 RF ablation procedures performed in 413 patients were evaluated. All procedures were performed in the same laboratory by the same group of physicians. Success rates for ablation of supraventricular tachycardia did not differ among the 3 age groups, ranging from 93% to 95%. Procedural aspects, including total procedure time, fluoroscopy time, and number of applications of RF energy also did not differ by age group. However, analysis of outcome and procedural complexity with respect to pathway location demonstrated that ablation of right free wall and septal accessory pathways was significantly more difficult than left free wall or slow pathway (success rates of 85% and 88% vs 97% and 98%, respectively, p = 0.01 and 0.02), irrespective of age. Additionally, right free wall pathways required significantly greater procedure time (mean = 5.1 hours), fluoroscopy time (mean = 78 minutes), and RF applications (median = 16) than ablations performed at other sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Relative rates of incorporation of esterified cholesterol into human very low density lipoproteins and low density lipoproteins. In vitro studies of two separate pathways.

It has been shown previously that there are two pathways by which the esterified cholesterol formed in human plasma in the reaction catalysed by lecithin: cholesterol acyltransferase may be delivered to very low density lipoproteins (VLDL) and low density lipoproteins (LDL): (a) an indirect pathway in which esterified cholesterol which was incorporated initially into high density lipoproteins (HDL) is transferred subsequently to VLDL and LDL in a process mediated by an esterified cholesterol transfer/exchange protein and (b) a direct pathway in which a small proportion of the esterified cholesterol formed in the lecithin:cholesterol acyltransferase reaction is delivered to VLDL and LDL directly from its site of synthesis via a pathway which bypasses the bulk HDL fraction. These present studies have been designed to examine the incorporation of esterified cholesterol into VLDL relative to that into LDL via each of these two pathways. It has been found that a delivery of esterified cholesterol from HDL to VLDL and LDL via the indirect pathway has a marked preference for VLDL over LDL; equating the concentrations of esterified cholesterol in the two fractions revealed an incorporation into VLDL which was 7-11 times greater than that into LDL. By contrast, delivery via the direct pathway showed a marginal preference for LDL over VLDL.

Adult↗
PubMed1986

The hepatic galactosyl receptor system: two different ligand dissociation pathways are mediated by distinct receptor populations.

After internalization of 125I-asialo-orosomucoid (ASOR) by isolated rat hepatocytes, ligand dissociates by two kinetically distinct pathways (Oka and Weigel, J. Biol. Chem. 257, 10,253, 1983). These slow and fast dissociation pathways correspond to two functionally different subpopulations of cell surface galactosyl receptors designated, respectively, State 1 and State 2 receptors. Freshly isolated cells or cells equilibrated below 24 degrees C express only State 1 receptors. Cells equilibrated at 37 degrees C express both State 1 and State 2 receptors. Ligand dissociation after internalization of surface-bound 125I-ASOR was measured using the permeabilizing detergent, digitonin. The slow dissociation pathway was mediated by State 1 receptors and was the only pathway expressed by cells which were freshly isolated or had been equilibrated at 24 degrees C. State 2 receptors are expressed at temperatures above about 20 degrees C, and both the fast and slow dissociation pathways occurred in cells equilibrated at 37 degrees C. State 2 receptors therefore mediate the rapid dissociation pathway. Dissociation and subsequent degradation of specifically bound ligand routed in either pathway were complete, respectively, within 3 and 6 hrs.

Animals↗
PubMed1995

Diquat-dependent protein carbonyl formation. Identification of lipid-dependent and lipid-independent pathways.

In a previous report on diquat-dependent oxidative damage in rat hepatic microsomes, protein oxidation, as measured by protein carbonyl (PC) formation, was observed in addition to lipid peroxidation (LP). Both phenomena were antioxidant sensitive. Inhibition of PC formation was somewhat surprising given the proposed mechanism of metal-catalyzed protein oxidation. Studies reported here examined diquat-dependent PC formation in greater detail. In rat hepatic microsomes, diquat-dependent thiobarbituric acid-reactive substances (TBARS) and PC formation were time and concentration dependent. In this system, LP was inhibited completely by U-74006F or U-78517G, whereas PC formation was inhibited only partially by these antioxidants. In an essentially lipid-free system consisting of purified rat hepatic cytochrome P450 reductase, BSA and an NADPH-generating system, PC formation was also observed, but was not antioxidant-sensitive. Under these conditions, minimal diquat-dependent TBARS formation was observed. The observation of relative antioxidant insensitivity is consistent with H2O2 (generated during the diquat redox cycle) catalyzing protein oxidation via a site-specific, metal-catalyzed mechanism. Thus, different pathways would appear to be involved in diquat-dependent PC formation in lipid-containing and lipid-free systems. Carbon tetrachloride induces LP following reductive activation to the trichloromethyl free radical, a pathway not directly involving H2O2 generation. In the microsomal system, CCl4 induced TBARS and PC formation, both of which were completely inhibitable by antioxidants. Taken together, these data suggest that diquat induces PC formation by lipid-dependent (antioxidant-sensitive) and lipid-independent (antioxidant-insensitive) pathways. In microsomes, both pathways contribute to diquat-dependent PC formation. Data for the lipid-independent pathway are consistent with the mechanism of metal-catalyzed protein oxidation proposed by Stadtman and colleagues (reviewed in Free Radic Biol Med 9: 315-325, 1990), while the lipid-dependent pathway is likely secondary to LP itself--via a Michael-type addition reaction between hydroxyalkenals and protein sulfhydryl groups, amino groups or other protein nucleophiles. The latter pathway is also responsible for carbon tetrachloride-dependent PC formation. Additional studies are in progress to further characterize the lipid-independent mechanism.

Animals↗
PubMed1990

Blockade of inhibition in a pathway with dual excitatory and inhibitory action unmasks a capability for LTP that is otherwise not expressed.

Long-term potentiation (LTP) can be readily elicited in a number of hippocampal pathways, but has not been seen in the dentate commissural pathway. The dentate commissural pathway is similar to the commissural/Schaffer collateral projection to CA1 except that it produces powerful inhibition that occurs nearly concurrently with the excitation. The present study evaluates whether this inhibition prevents the pathway from expressing LTP. Acute neurophysiological experiments were carried out in urethane anesthetized rats. To locally block inhibition in the dentate gyrus, a recording micropipette filled with 8 mM bicuculline was positioned in the dentate gyrus. A control saline-filled micropipette was positioned nearby. The commissural pathway was activated by stimulating electrodes in the contralateral CA3/CA4 region. Brief high-frequency stimulation of the commissural pathway reliably elicited LTP at the bicuculline electrode but not at the control electrode. This LTP required a threshold level of stimulation for its initiation, suggesting that like most other examples of LTP, the LTP in the commissural system depended upon activation of a voltage-dependent receptor. The high-frequency stimuli used to induce LTP produced an extracellular negativity at the bicuculline electrode that was not present at the control electrode. This negative potential was selectively blocked by ketamine and MK801, suggesting that the negative potential reflects N-methyl-D-aspartate (NMDA) receptor activation. Taken together, these results suggest that LTP is not normally expressed by the dentate commissural pathway because the simultaneous inhibition prevents the depolarization-related relief of Mg2+ blockade of the NMDA receptor.

Animals↗
PubMed1988

Cell death delineates axon pathways in the hindlimb and does so independently of neurite outgrowth.

We wished to know whether the cell death and phagocytosis seen near the outgrowing nerve front in the hindlimb delineate axon pathways and, if so, whether the cells died only in the presence of growth cones. We unilaterally deleted the lumbosacral neural tube and reconstructed the patterns of neurite outgrowth and phagocytes during the stage when neurites first begin to colonize the thigh. In the control limbs, sensory and motor nerve pathways coincided with sites of phagocytosis, including those pathways that had yet to be colonized by growth cones. For instance, phagocytes were clustered at foci within the muscle masses where muscle nerves form a day later. However, they were not seen in adjacent, nonpathway regions such as posterior sclerotome or dorsal and ventral to the region of the plexus in which axons extend only posteriorly. Phagocytes were also seen in defined regions that are probably inaccessible to growth cones because they are too distant from pathways (i.e., subjacent to the apical ectodermal ridge) or express substances that are typical of precartilagenous tissues which may prohibit axon advance. In the experimental limbs, we conservatively estimated that neurite outgrowth was reduced to less than one-tenth (neurites were visible only with electron microscopy) or less than one-third of normal. Outgrowth extended less far distally and, in half the cases, motor innervation was completely abolished. Despite the extensive reduction in neurite outgrowth, the distribution of phagocytes was indistinguishable from that of the control side. Furthermore, the number of phagocytes did not differ significantly. We conclude that cell death delineates axon pathways remarkably well and does so without an interaction with growth cones; it is an independent characteristic of the axonal pathways and may be directly or indirectly important to axonal pathfinding. This is the first identification of a feature that characterizes prospective nerve pathways in the hindlimb.

Animals↗
PubMed1983

Intracellular membrane traffic: pathways, carriers, and sorting devices.

Multiple pathways of intracellular membrane traffic have been detected in various cell types. The major established routes are (a) the exocytosis pathway, utilized in secretory cells for the discharge of secretory products, and which is also believed to be used for delivery of intrinsic membrane glycoproteins in all cell types; (b) the plasmalemma to Golgi route, also highly developed in secretory cells, which is believed to be utilized for the recovery and recycling of the membranes of containers used in packaging of secretory products (i.e., secretory granules or vesicles); (c) the lysosomal pathway, which is available in all cells but is the major route utilized in phagocytic cells; (d) the transcellular route, which represents the major type of traffic encountered in nonfenestrated, capillary endothelial cells and also appears to be the preferred route for the transport of immunoglobulins (intact) across cells; and (e) the biosynthetic pathways used for transport of secretory products, lysosomal enzymes, and membrane proteins from the ER to the Golgi complex and for transport of lysosomal enzymes from the Golgi complex to lysosomes in all cell types. It has become clear that cells repeatedly reutilize or recycle the vesicular membranes involved in carrying out these various transport operations. Clathrin-coated vesicles have been found to be involved in transport along all the routes detected so far, suggesting that there are multiple populations of coated vesicles with different transport functions in every cell. It has become clear that considerable sorting of membrane constituents and ligands takes place at the plasmalemma (receptor-mediated uptake), in the Golgi complex, and in endosomes. The Golgi complex is the intracellular site where much of the biosynthetic and recycling membrane traffic converges and where products are sorted and directed to their correct destinations. In summary, we have become aware of the existence of multiple pathways of membrane traffic and of the extensive reutilization or recycling of membranes that occurs in cells. The basic pathways are similar in all cells except that some are emphasized or deemphasized according to the predominant function and organization of a given cell type. What now remains to be done is to determine how these transporting membranes and the membranes of the receiving compartments are constructed, how their specific interactions are controlled, and how individual cell types utilize these pathways to carry out their specific functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.

Two interleukin-2 receptor-dependent signaling pathways have thus far been identified: the c-fos/c-jun induction pathway mediated by src family protein-tyrosine kinases and the c-myc induction pathway. Here, we provide evidence for the existence of a third, rapamycin-sensitive pathway, which results in the induction of another proto-oncogene, bcl-2. In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway. We also provide evidence that epidermal growth factor receptor signaling may act through the same pathway that involves p56lck. These studies demonstrate a novel approach to dissecting signaling pathways regulating cellular proliferation.

Animals↗
PubMed1994

Electrophysiologic demonstration of anterograde fast and slow pathways within the His bundle in patients with normal intraventricular conduction.

Electrophysiological evidence of functional longitudinal dissociation has been shown in different structures of the normal conduction system of the heart and in anomalous atrioventricular (AV) pathways. The typical sudden fast-to-slow jump phenomenon, which is commonly observed in patients with dual AV nodal pathways, has not been demonstrated so far within the normal His bundle. Herein we report unusual electrophysiological properties of the His bundle in two patients with normal intraventricular conduction. Of 86 patients with discontinuous anterograde AV function curves, programmed atrial stimulation revealed dual anterograde His bundle pathways in only 2 (2.3%) patients. Extrastimuli introduced at critically timed coupling intervals produced a sudden marked increase in H2-V2 interval suggesting failure of fast pathway with conduction proceeding through a slower pathway with shorter refractory period. With further decreasing coupling intervals, the second H2-V2 curve showed decremental conduction which allowed a type II gap phenomenon in the right bundle branch to occur in one of the patients. No echo beats were observed. These results provide the first electrophysiological demonstration, in patients with normal intraventricular conduction, of anterograde failure of a fast His bundle pathway with subsequent conduction through a slow His bundle pathway. His bundle duality was manifested by dual conduction times and refractory periods. These observations further expand our knowledge on the electrophysiologic properties of the His bundle.

Atrial Fibrillation↗
PubMed1995

Flux analysis of microbial metabolic pathways using a visual programming environment.

This paper describes the use of a visual programming environment (LabVIEW) for the flux analysis of metabolic pathways. Representations of metabolic pathways are constructed in software from individual reaction elements (icons) which are linked together to indicate potential flux routes. Off-line bioprocess data are then used to supply the inputs and outputs to the metabolic pathway and the pathway fluxes are calculated. The metabolic system can be modelled at different levels of complexity and new pathways can be inserted into existing models. To illustrate this, flux analyses are performed on three Escherichia coli mutants with metabolic pathway deletions and insertions. The first analysis looks at organic acid production and the second at the effect of the presence in E. coli of an engineered pathway for toluene degradation.

Acetates↗
PubMed1996

On the analysis of the inverse problem of metabolic pathways using artificial neural networks.

Here we develop the use of artificial neural networks for solving the inverse metabolic problem, in other words, given a set of steady-state metabolite levels and fluxes in a pathway of known structure to obtain the parameters of the system, in this case the enzymatic limiting rate and Michaelis constants. This requires two main procedures: first the development of a computer program with which one can model metabolism in the forward direction (i.e. given the internal and parameters to determine the steady-state fluxes and metabolite concentrations), and second, given arrays of associated parameters and variables thereby obtained, to exploit artificial neural networks to form a model capable of obtaining the parameters from the variables. We studied 2-step pathways exhibiting first-order kinetics, 2-step pathways exhibiting reversible Michaelis-Menten kinetics and then 3-step pathways (again exhibiting reversible Michaelis-Menten kinetics), modelled using the program Gepasi. Whilst it was fairly easy for the networks to learn most of the parameters in the 2-step pathway, it was found helpful for the Michaelis-Menten case to vary the concentration of the starting pathway substrate for each set of internal parameters, and to train separate networks for each parameter. Some parameters were much easier to learn than others, reverse K(m) and V(max) values normally being the most difficult. For the 3-step pathway learning sometimes required as much as 3 days, and occasionally convergence was not obtained. Overall, neural networks of the present type, with fully interconnected feedforward architectures and trained according to the backpropagation algorithm, scaled poorly as the problem size was increased.

Algorithms↗
PubMed1992

Pathway selection by ectopic motoneurons in embryonic zebrafish.

Primary motoneurons in embryonic zebrafish innervate cell-specific muscles. During pathfinding, motoneuronal growth cones encounter three distinct regions: a common pathway, a choice point, and separate cell-specific pathways. To learn whether the order in which these regions are encountered influences pathway choice, we transplanted individual motoneurons to the choice point region. These cells selected their appropriate cell-specific pathways. Thus, the sequence in which pathway regions are encountered may not be important for accurate path-finding, and the cell-specific pathways may be delineated by distinct cues that individual growth cones recognize. Moreover, these cues are unlikely to be general ones, since primary sensory neurons transplanted to the same location do not extend growth cones along the motoneuronal pathways.

Animals↗
PubMed2004

A high-performance liquid chromatography method for the analysis of intermediates of the deoxyxylulose phosphate pathway.

A sensitive and versatile ion pair radio high-performance liquid chromatography (HPLC) method for the investigation of the deoxyxylulose phosphate (DXP) pathway has been developed, allowing the simultaneous separation of phosphorylated, nonphosphorylated, and nucleotide moieties bearing intermediates. Moreover, this method addresses the problem of separating the isomers isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP). Because the majority of the intermediates of this isoprenoid pathway lack a chromophore, the combination with an on-line radiodetector provides a highly sensitive tool for their detection. Chromoplasts isolated from Capsicum annuum and Narcissus pseudonarcissus served as model systems for the testing of the analytical procedures after the application of radiolabeled precursors. This HPLC system, which represents an improvement in analytical methods developed for the analysis of the mevalonic acid pathway, should be easily adaptable to other plant and bacterial systems and should permit further elucidation of the regulatory mechanisms that control the flow of intermediates through the DXP pathway and the coordination with related metabolic pathways. Moreover, the system can serve as an analytical tool in the screening for inhibitors of this pathway, allowing the development of new antibiotics as well as herbicides, because this pathway is absent in vertebrates.

Capsicum↗
PubMed2006

C-phycocyanin transcriptionally regulates uPA mRNA through cAMP mediated PKA pathway in human fibroblast WI-38 cells.

We have previously demonstrated the efficacy of c-phycocyanin in up-regulation of urokinase-type plasminogen activator (uPA) in bovine endothelial cell line. However, the mechanism of action and pathway elucidation in uPA regulation is unclear. In experiments reported here, we have investigated the mechanism of action of c-phycocyanin (c-pc) induced uPA gene modulation in human fibroblast (WI-38) cell line. ELISA test confirmed that c-pc increased the uPA antigen whereas PAI-1 antigen level was unaffected. Treatment of cells with c-pc significantly (P<0.05) enhanced the uPA mRNA level in a dose (50 microg/ml) and time dependent (up to 4 h) manner. This effect of c-pc was abolished by treatment with dichloro-1-beta-D-ribofuranosyl benzamidazole (DRB) (10 microg/ml). Co-treatment of c-pc with 200 microg/ml cycloheximide (CHX), translation inhibitor, resulted in over accumulation of uPA mRNA. These results suggest that uPA induction by c-pc is transcriptionally regulated and does not require de novo protein synthesis. We also provide evidence that c-pc stimulates uPA gene through cAMP dependent pathway as adenylyl cyclase (AC) inhibitor, dideoxyadenosine (DDA) significantly inhibited the uPA mRNA expression and co-treatment with adenylyl cyclase analogue, dBcAMP recovered the effect of c-pc on gene activity. Furthermore, the present investigation provides evidence on the regulatory pathway involved in the c-pc stimulus. C-pc induced uPA expression was completely inhibited by PKA inhibitor (KT 5200), indicating the regulation is dependent on PKA pathway. Elimination of PKC pathway components by prolonged incubation with excess amount of phorbol 12-myristate 13-acetate (PMA) failed to abolish the c-pc effect on uPA expression indicating the regulation is independent of PKC pathway. Taken together, our data indicate that uPA gene regulation by c-pc is transcriptionally controlled through cAMP mediated PKA pathway.

Cells, Cultured↗
PubMed2004

Protein secretion through autotransporter and two-partner pathways.

Two distinct protein secretion pathways, the autotransporter (AT) and the two-partner secretion (TPS) pathways are characterized by their apparent simplicity. Both are devoted to the translocation across the outer membrane of mostly large proteins or protein domains. As implied by their name, AT proteins contain their own transporter domain, covalently attached to the C-terminal extremity of the secreted passenger domain, while TPS systems are composed of two separate proteins, with TpsA being the secreted protein and TpsB its specific transporter. In both pathways, the secreted proteins are exported in a Sec-dependent manner across the inner membrane, after which they cross the outer membrane with the help of their cognate transporters. The AT translocator domains and the TpsB proteins constitute distinct families of protein-translocating, outer membrane porins of Gram-negative bacteria. Both types of transporters insert into the outer membrane as beta-barrel proteins possibly forming oligomeric pores in the case of AT and serve as conduits for their cognate secreted proteins or domains across the outer membrane. Translocation appears to be folding-sensitive in both pathways, indicating that AT passenger domains and TpsA proteins cross the periplasm and the outer membrane in non-native conformations and fold progressively at the cell surface. A major difference between AT and TPS pathways arises from the manner by which specificity is established between the secreted protein and its transporter. In AT, the covalent link between the passenger and the translocator domains ensures the translocation of the former without the need for a specific molecular recognition between the two modules. In contrast, the TPS pathway has solved the question of specific recognition between the TpsA proteins and their transporters by the addition to the TpsA proteins of an N-proximal module, the conserved TPS domain, which represents a hallmark of the TPS pathway.

Amino Acid Sequence↗
PubMed2005

A systems biology approach for the study of cumulative oncogenes with applications to the MAPK signal transduction pathway.

The Extracellular signal Regulated Kinase (ERK) pathway is one of the most well-studied signaling pathways in cell cycle regulation. Disruption in the normal functioning of this pathway is linked to many forms of cancer. In a previous study [D.K. Pant, A. Ghosh, Automated oncogene detection in complex protein networks, with applications to the MAPK signal transduction pathway, Biophys. Chem. 113 (2005) 275-288.], we developed a novel approach to predict single point mutations that are likely to cause cellular transformation in signaling transduction networks. We have extended this method to study disparate pair mutation in enzyme/protein interactions and in expression levels in signal transduction pathway and have applied it to the MAPK signaling pathway to study how synergistic or cooperative mutation within signaling networks acts in unison to cause malignant transformation. The method provides a quantitative ranking of the modifier pair of ERK activation. It is seen that the highest ranking single point mutations comprise the highest ranking pair mutations. We validate some of our results with experimental literature on multiple mutations. A second order sensitivity analysis scheme is additionally used to determine the effect of correlations among mutations at different sites in the pathways.

Enzyme Activation↗