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PubMed2005

Inhibition of MAPK and NF-kappa B pathways is necessary for rapid apoptosis in macrophages infected with Yersinia.

Macrophages respond to infection with pathogenic Yersinia species by activating MAPK- and NF-kappaB-signaling pathways. To counteract this response, Yersiniae secrete a protease (Yersinia outer protein J (YopJ)) that is delivered into macrophages, deactivates MAPK- and NF-kappaB-signaling pathways, and induces apoptosis. NF-kappaB promotes cell survival by up-regulating expression of several apoptosis inhibitor genes. Previous studies show that deactivation of the NF-kappaB pathway by YopJ is important for Yersinia-induced apoptosis. To determine whether deactivation of the NF-kappaB pathway is sufficient for Yersinia-induced apoptosis, two inhibitors of the NF-kappaB pathway, IkappaBalpha superrepressor or A20, were expressed in macrophages. Macrophages expressing these proteins were infected with Yersinia pseudotuberculosis strains that secrete functionally active or inactive forms of YopJ. Apoptosis levels were substantially higher (5- to 10-fold) when active YopJ was delivered into macrophages expressing IkappaBalpha superrepressor or A20, suggesting that deactivation of the NF-kappaB pathway is not sufficient for rapid Yersinia-induced apoptosis. When macrophages expressing A20 were treated with specific inhibitors of MAPKs, similar levels of apoptosis (within approximately 2-fold) were observed when active or inactive YopJ were delivered during infection. These results suggest that MAPK and NF-kappaB pathways function together to up-regulate apoptosis inhibitor gene expression in macrophages in response to Yersinia infection and that YopJ deactivates both pathways to promote rapid apoptosis. In addition, treating macrophages with a proteasome inhibitor results in higher levels of infection-induced apoptosis than can be achieved by blocking NF-kappaB function alone, suggesting that proapoptotic proteins are stabilized when proteasome function is blocked in macrophages.

Animals↗

PubMed2005

Overview of cell death signaling pathways.

Apoptosis plays an important role in development and maintenance of tissue homeostasis. Intensive efforts have been made to explore the molecular mechanisms of the apoptotic signaling pathways including the initiation, mediation, execution and regulation of apoptosis. Caspases are central effectors of apoptosis. Cells undergo apoptosis through two major pathways, namely the extrinsic pathway (death receptor pathway) or the intrinsic pathway (the mitochondrial pathway). Finally, the contents of dead cells are packaged into apoptotic bodies, which are recognized by neighboring cells or macrophages and cleared by phagocytosis. Cellular apoptosis is tightly controlled by a complex regulatory networks including balancing pro-survival signals. De-regulation of apoptosis may lead to pathological disorders such as developmental defects, autoimmune diseases, neurodegeneration or cancer. Increasing attention is being focused on alternative signaling pathways leading to cell death including necrosis, autophagy, and mitotic catastrophe. Understanding of cell death signaling pathways is relevant to understanding cancer and to developing more effective therapeutics.

Animals↗

PubMed2003

A relationship between the mevalonate pathway and isoprenoid production in actinomycetes.

Most Streptomyces strains are equipped with only the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for the formation of isopentenyl diphosphate. In addition to this pathway, some Strepromyces strains have the mevalonate pathway to produce terpenoid antibiotics. We have previously shown that a gene cluster for biosynthesis of terpentecin, a diterpene antibiotic, was located in adjacent the mevalonate pathway gene cluster. In this study, a mevalonate pathway gene cluster was cloned from Actinoplanes sp. strain A40644, an isoprenoid antibiotic BE-40644 producer, to examine whether the mevalonate pathway genes and isoprenoid biosynthetic genes are clustered in genomic DNA. By sequencing flanking regions a probable BE-40644 biosynthetic gene cluster was found in the downstream region of the mevalonate pathway gene cluster. Heterologous expression of a 9-kb fragment confirmed that a set of the BE-40644 biosynthetic genes was involved in the fragment. This result suggested that the presence of the mevalonate pathway might be a good landmark to detect the production of isoprenoid compounds by actinomycetes.

Actinobacteria↗

PubMed1999

Sending signals from the synapse to the nucleus: possible roles for CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth.

The ability to learn and form memories depends on specific patterns of synaptic activity and is in part transcription dependent. However, the signal transduction pathways that connect signals generated at synapses with transcriptional responses in the nucleus are not well understood. In the present report, we discuss three signal transduction pathways: the Ca(2+)/calmodulin-dependent kinase (CaMK) pathway, the Ras/ERK pathway, and the SAPK pathways that might function to couple synaptic activity to long-term adaptive responses, in part through the regulation of new gene expression. Evidence suggests that these pathways become activated in response to stimuli that regulate synaptic function such as the influx of extracellular Ca(2+) and certain neurotrophin growth factors such as brain-derived neurotrophic factor. Once activated, the CaMK, Ras/ERK, and SAPK pathways lead to the phosphorylation and activation of transcription factors in the nucleus such as the cyclic AMP response element binding protein (CREB). Genes regulated by CREB or other transcription factor targets of the CaMK, Ras/ERK, and SAPK pathways could mediate important adaptive responses to changes in synaptic activity such as changes in synaptic strength and the regulation of neuronal survival and death.

Animals↗

PubMed1999

[Accessory pathways and supraventricular tachycardia].

Accessory pathways represent abnormalities of atrioventricular conduction. According to the course and the site of insertion they can be divided into atrioventricular (AV), atrio-His, atriofascicular, nodoventricular, nodofascicular and fasciculoventricular. AV accessory pathways are the most common form. An anterior, lateral and posterior localisation of AV accessory pathways can be distinguished in the left and right free wall. Atriofascicular accessory pathways usually exhibit antegrade conduction with AV node-like decremental properties. Right atriofascicular accessory pathways are involved in most cases of Mahaim-type tachycardias. AV re-entrant tachycardia based on the presence of AV accessory pathway is mostly orthodromic, less commonly antidromic. The orthodromic AV re-entrant tachycardia based on the pathway exhibiting decremental retrograde conduction is known as permanent junctional reciprocating tachycardia. Patients with Wolff-Parkinson-White syndrome often demonstrate an atrial fibrillation. As conduction over an accessory pathway during atrial fibrillation can be rapid, some of them are at a high risk of ventricular fibrillation and sudden cardiac death. (Ref. 26.)

Heart Conduction System↗

PubMed1999

[Catheter ablation of accessory pathways in patients with congenital cardiopathies].

The catheter ablation procedure in patients with accessory pathways and congenital heart defects can potentially become complicated because of abnormal anatomy and atypical conduction system. Eight patients ranging in age from 4.5 months to 18 years with accessory pathways and congenital heart defects underwent radiofrequency ablation. The cardiac diseases were diagnosed as Ebstein anomaly (n = 3), cardiac rhabdomyomas (n = 1), double outlet right ventricle (n = 1), endocardial cushion defect, partial form (n = 1), repaired Fallot's tetralogy (n = 1) and interventricular septal defect (n = 1). Six patients had manifest Wolff-Parkinson-White syndrome and 2 had concealed pathways. One patient with Ebstein anomaly had multiple accessory pathways. Radiofrequency ablation was initially successful in eight of the nine accessory pathways (89%). Two procedures were performed in one patient for pathway recurrence. Procedure was unsuccessful in 1 patient with Ebstein anomaly who later had surgical interruption of the accessory pathway. After a mean follow-up of 30.9 +/- 16.4 months, six of the 7 patients in which pathways were successfully ablated are tachycardia-free. One patient had late recurrence of tachycardia and is well controlled by propafenone.

Adolescent↗

PubMed2000

Disposition of glutathione conjugates in rats by a novel glutamic acid pathway: characterization of unique peptide conjugates by liquid chromatography/mass spectrometry and liquid chromatography/NMR.

With the advent of liquid chromatography/mass spectrometry and liquid chromatography/NMR, it has become easier to characterize metabolites that were once difficult to isolate and identify. These techniques have enabled us to uncover the existence of an alternate pathway for the disposition of glutathione adducts of several structurally diverse compounds. Studies were carried out using acetaminophen as a model compound to investigate the role of the glutamic acid pathway in disposition of the glutathione adducts. Although the mercapturic acid pathway was the major route of degradation of the glutathione adducts, it was found that the conjugation of the glutathione, cysteinylglycine, and cysteine adducts of acetaminophen with the gamma-carboxylic acid of the glutamic acid was both interesting and novel. The coupling of the glutathione adduct and the products from the mercapturic acid pathway with the glutamic acid led to unusual peptide conjugates. The natures of these adducts were confirmed unequivocally by comparisons with synthetic standards. This pathway (addition of glutamic acids) led to larger peptides, in contrast to the mercapturic acid pathway, in which the glutathione adducts are broken down to smaller molecules. The enzyme responsible for the addition of glutamic acid to the different elements of the mercapturic acid pathway is currently unknown. It is postulated that the gamma-carboxylic acid is activated (perhaps by ATP) before enzymatic addition to the alpha-amino group of cysteine or glutamate takes place. The discovery of these peptide conjugates of acetaminophen represents a novel disposition of glutathione adducts of compounds. The formation of such conjugates may represent yet another pathway by which drugs could produce covalent binding via their reactive intermediates.

Acetaminophen↗

PubMed2001

Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation.

The data presented here demonstrate that sympathetic neurons have the potential to activate two alternative caspase-dependent pathways either of which is capable of mediating death induced by NGF deprivation and that these neurons have the potential to switch from one pathway to the other. The presence of these two alternative pathways to trophic factor deprivation-induced death may have implications for ensuring the correct development of the nervous system. In wild-type neurons, a caspase-2-dependent pathway is required for death, and a caspase-9-dependent pathway appears to be suppressed by endogenous inhibitors of apoptosis proteins (IAPs). In contrast, for caspase-2-null neurons, death is dependent on the caspase-9 pathway. The mechanism underlying the shift is the result of a threefold compensatory elevation of caspase-9 expression and a doubling of levels of direct IAP binding protein with low pI/(DIABLO)/second mitochondria-derived activator of caspase (Smac), an IAP inhibitor, both at the mRNA and protein levels [corrected]. These findings resolve seemingly discrepant findings regarding the roles of various caspases after NGF deprivation and raise a cautionary note regarding the interpretation of findings with caspase-null animals. The choice of the death-mediating caspase pathway in the sympathetic neurons is thus dependent on the regulated relative expression of components of the pathways including those of caspases, IAPs, and IAP inhibitors.

Animals↗

PubMed2001

Biosynthetic pathway of insect juvenile hormone III in cell suspension cultures of the sedge Cyperus iria.

In most insect species, juvenile hormones regulate critical physiological processes such as metamorphosis and reproduction. In insects, these sesquiterpenoids are synthesized by retrocerebral endocrine organs, the corpora allata, via the classical mevalonate (MVA) pathway. One of these compounds, juvenile hormone III (JH III), has also been identified in the sedge Cyperus iria. In higher plants, biosynthesis of the sesquiterpenoid backbone may proceed through two distinct pathways: the MVA pathway or the 2C-methyl erythritol 4-phosphate pathway or through a combination of both pathways. Cell suspension cultures of C. iria were used to elucidate the biosynthetic pathway of JH III in the plant. Enzyme inhibition and labeling studies conclusively demonstrated that the biosynthesis of the sesquiterpenoid backbone of JH III proceeds via the MVA pathway. Inhibitor and precursor feeding studies also suggest that later steps of JH III biosynthesis in C. iria are similar to the insect pathway and that the final enzymatic reaction in JH III biosynthesis is catalyzed by a cytochrome P(450) monooxygenase.

Aldose-Ketose Isomerases↗

PubMed2001

[Activation of PKA pathway inhibits reactivity of human myeloma cell line-U266 to IL-6].

OBJECTIVE: To study the effects of PKA pathway activation on the biological function and signal transduction of IL-6 in a human myeloma cell line-U266. METHODS: The effect of IL-6 on the growth of U266 cells was shown by MTT; electrophoretic mobility shift assay (EMSA) was used to detect the activation of two transcription factors(TFs)-STAT3 and the NF-IL-6 by IL-6, which were involved in the JAK/STAT and Ras/NF-IL-6 signal transduction pathways. Then, the cells were treated with IL-6 and Forskolin (FK), an agonist of the PKA pathway. The changes in the cell growth and activation of the two TFs were exhibited by MTT and EMSA. RESULTS: (1) IL-6 could promote the proliferation of U266 cells, (2) both JAK/STAT and Ras/NF-IL-6 signal transduction pathways were activated by IL-6 in the U266 cells and (3) Cell proliferation and activation of the two IL-6 signal transduction pathways were inhibited by Forskolin; down-regulating the actiration of these two signal transduction pathways at the same time. CONCLUSION: The inhibition of cell growth, mediated by the activation of the PKA pathway, is related to the down-regulated activation of the two IL-6 signal transduction pathways.

CCAAT-Enhancer-Binding Protein-beta↗

PubMed1992

[Slow and fast AV nodal pathways in tachycardia complicating Wolff-Parkinson-White syndrome: report of a case].

Electrophysiologic studies in a patient with intermittent ventricular pre-excitation revealed several types of paroxysmal narrow-QRS tachycardia (PSVT). One type of PSVT was characterized by normal retrograde atrial sequences with P waves occurring simultaneously with QRS. This type of PSVT reflected AV nodal reentry with anterograde slow pathway and retrograde fast pathway conduction. A second PSVT reflected alternation of anterograde fast and slow AV nodal pathway conduction and retrograde anomalous pathway conduction. A third PSVT reflected anterograde slow AV nodal pathway and retrograde anomalous pathway conduction. Moreover, discontinuous AV nodal conduction curves (A1A2/H1H2), characteristic of dual AV nodal pathway conduction, were obtained with programmed atrial extra stimulation. These observations suggest that dual AV nodal pathway conduction can coexist with abnormal bypass tract and can be the cause of PSVT in patients with Wolff-Parkinson-White syndrome.

Adult↗

PubMed1992

Radiofrequency catheter ablation of accessory pathways.

One hundred five patients with an accessory atrioventricular pathway underwent catheter ablation of the pathway using radiofrequency current. There were 79 accessory pathways located on the left and 32 on the right side of the heart. In patients with right-sided pathways ablation was attempted via a catheter positioned at the atrial aspect of the tricuspid annulus. In patients with a left-sided free-wall accessory pathway a novel approach was utilized in which the ablation catheter was positioned in the left ventricle directly below the mitral annulus. Accessory pathway conduction was permanently abolished in 93 patients (89%). Failures were mainly due to inadequate catheters used initially. It is concluded that catheter ablation of accessory atrioventricular pathways using radiofrequency current is an effective and safe therapeutic modality for patients with symptomatic tachyarrhythmias mediated by these pathways.

Adult↗

PubMed1992

[Radiofrequency energy as treatment for arrhythmias in patients with accessory atrioventricular pathways].

OBJECTIVE: Evaluation of the use of radiofrequency energy to interrupt accessory atrioventricular pathways. DESIGN: Prospective study. SETTING: University Hospital Maastricht. METHOD: The outcome is presented of radiofrequency catheter ablation of accessory atrioventricular pathways in our first 50 consecutive patients, with a total of 54 accessory pathways. All but one patient suffered from symptomatic tachycardias. A catheter electrode was positioned next to the accessory pathway and 30 second pulses of 40 W radiofrequency energy were used to interrupt the connection. RESULTS: Complete block in conduction was accomplished in 44/54 (81%) of accessory pathways. No complications occurred. Success rate, procedure time and radiation dose were found to be related to the location of the accessory connection. The highest success rate was found in left free wall pathways (24/26; 92%), the lowest in right lateral pathways which seldom occur (1/4; 25%). The total procedure took 1-6 hours. The maximal duration of radiographic imaging was 2.5 hours. CONCLUSION: Although insufficient information on long-term efficacy is available, current results support the use of radiofrequency ablation of accessory pathways in institutions with expertise in the invasive management of cardiac arrhythmias. Technical improvements leading to reduction in procedure time and radiation dose will facilitate acceptance of this technique by patient and operator.

Adolescent↗

PubMed2002

In silico metabolic pathway analysis and design: succinic acid production by metabolically engineered Escherichia coli as an example.

The intracellular metabolic fluxes can be calculated by metabolic flux analysis, which uses a stoichiometric model for the intracellular reactions along with mass balances around the intracellular metabolites. In this study, we have constructed in silico metabolic pathway network of Escherichia coli consisting of 301 reactions and 294 metabolites. Metabolic flux analyses were carried out to estimate flux distributions to achieve the maximum in silico yield of succinic acid in E. coli. The maximum in silico yield of succinic acid was only 83% of its theoretical yield. The lower in silico yield of succinic acid was found to be due to the insufficient reducing power, which could be increased to its theoretical yield by supplying more reducing power. Furthermore, the optimal metabolic pathways for the production of succinic acid could be proposed based on the results of metabolic flux analyses. In the case of succinic acid production, it was found that pyruvate carboxylation pathway should be used rather than phosphoenolpyruvate carboxylation pathway for its optimal production in E. coli. Then, the in silico optimal succinic acid pathway was compared with conventional succinic acid pathway through minimum set of wet experiments. The results of wet experiments indicate that the pathway predicted by in silico analysis is more efficient than conventional pathway.

Computational Biology↗

PubMed2003

Deregulation of the TP53/p14ARF tumor suppressor pathway in low-grade diffuse astrocytomas and its influence on clinical course.

PURPOSE: The chromosome 9p21 region harbors three tumor suppressor genes, p14(ARF), p15(INK4b), and p16(INK4a), all of which can be targets for hypermethylation-associated inactivation in low-grade gliomas. p16(INK4a) and p15(INK4b) are critically involved in the RB1 pathway, whereas p14(ARF) acts as an upstream regulator of the TP53 pathway. The role of each tumor suppressor pathway in low-grade diffuse astrocytomas and their relationships with clinical behavior remain to be elucidated. EXPERIMENTAL DESIGN: We assessed the alterations of the RB1/CDK4/p16(INK4a)/p15(INK4b) and the TP53/MDM2/p14(ARF) pathways in 46 WHO grade II astrocytomas and analyzed their impact on prognosis. RESULTS: The TP53/MDM2/p14(ARF) pathway was altered in 32 of 46 cases (70%) by either TP53 mutation (25 cases) or p14(ARF) methylation (9 cases). The RB1/CDK4/p16(INK4a)/p15(INK4b) pathway was disrupted in 6 of 46 cases (13%) by either RB1 methylation (1 case), p16(INK4a) methylation (3 cases), or p15(INK4b) methylation or homozygous deletion (3 cases). Generally speaking, individual tumors thus tended to display alteration of only one component from both pathways. Any independently analyzed genetic alteration failed to provide statistically prognostic information. The alternate or simultaneous presence of TP53 mutation and p14(ARF) methylation emerged as a univariate predictor of a shorter progression-free survival (P = 0.0456) but was not statistically significant when age and extent of surgery were included in the analysis. CONCLUSIONS: Alternative disruption of the TP53/p14(ARF) pathway represents a frequent event in low-grade diffuse astrocytomas and correlates with an unfavorable clinical course. However, its value is unlikely to include prognostic utility that is independent of other conventional prognostic factors.

Adult↗

PubMed2003

Targeting PI3K-AKT pathway for cancer therapy.

The phosphatidilinositol 3-kinase/protein kinase B (PI3K-AKT) pathway presents an exciting new target for molecular therapeutics. While exhibiting great promise, additional preclinical and clinical studies will be required to determine how best to target this pathway to improve patient outcome. A number of questions need to be answered prior to the implementation into patient care practices. As described below, the PI3K-AKT pathway regulates a broad spectrum of cellular processes, some of which are necessary to maintain normal physiological functions, which potentially contribute to the toxicity of the drugs targeting the pathway. Elucidation of the precise function of the PI3K-AKT isoforms, could promote the development of isoform specific approaches to provide a selective action on tumor cells. However, whether this will be possible due to conservation of structural domains is not yet clear. Inhibition of the PI3K-AKT pathway at multiple sites or a combination with inhibitors of different signaling pathways may allow the development of an acceptable therapeutic index for cancer management. Further, inhibition of the PI3K-AKT pathway combined with conventional chemotherapy or radiation therapy may provide a more effective strategy to improve patient outcome. As molecular therapeutics target the underlying defects in patient tumors, molecular diagnostics are required to identify patients with particular genetic aberrations in the pathway. It will be critical to provide adequate therapeutic strategies tailored to each patient. In addition, patients with different genetic backgrounds or in different health conditions could respond adversely to particular therapeutics. Therefore, identification of patients for particular drugs based on the underlying genetic defects in the tumor as well as the characteristics of the host would be of benefit for improving patient outcome. Linking the targeted therapeutics to molecular imaging approaches will determine appropriate biologically relevant dose for patients. It will also define expected tumor responsiveness and eventually will improve efficacy and decrease toxicity. In this regard, personalized molecular medicine is likely to soon provide effective cancer treatment.

Animals↗

PubMed2004

Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways.

Staurosporine has long been used in vitro as an initiator of apoptosis in many different cell types, but the mechanism involved remains poorly understood. In the present study, we have examined the apoptosis-inducing potential of staurosporine in cultured melanoma cell lines and dissected the staurosporine-induced apoptotic signaling pathway. We report that although staurosporine activated Bax and the mitochondrial caspase-dependent apoptotic pathway, it also induced apoptosis of melanoma by caspase-independent pathways. The caspase-dependent apoptotic pathway was activated relatively soon after exposure to staurosporine and was associated with release of cytochrome c and Smac/DIABLO from mitochondria and cleavage of poly(ADP-ribose) polymerase and inhibitor of caspase-activated DNase. This pathway was inhibitable by broad caspase inhibitors. A second apoptotic pathway that appeared to be involved in late apoptotic events was caspase independent in that inhibitors of caspases did not prevent the late onset of apoptosis. Overexpression of Bcl-2 inhibited the early onset of apoptosis but not the later, caspase-independent pathway. Apoptosis-inducing factor may be responsible for the late apoptotic execution in that its translocation from mitochondria into the nucleus coincided with the late onset of apoptosis and could not be inhibited by either a pan-caspase inhibitor or overexpression of Bcl-2. Our results indicate that staurosporine is able to bypass resistance of melanoma cells to mitochondrial caspase-dependent apoptotic pathways; hence, derivatives of staurosporine may warrant further evaluation either alone or with other apoptosis-inducing agents.

Apoptosis↗

PubMedDate not supplied

A comparison of response to cisplatin, radiation and combined treatment for cells deficient in recombination repair pathways.

The responses of cells with mutated DNA repair pathways were compared for cisplatin, radiation and combination treatments. The knockout of the nonhomologous endjoining (NHEJ) pathway resulted in increased radiation sensitivity, but no change in cisplatin response in the mouse cells and increased radiosensitivity but decreased cisplatin sensitivity in chicken cells. The mutation of the homologous recombination repair (HR) pathway through XRCC3 in CHO cells resulted in increased radiation and cisplatin sensitivity and to a lesser extent for the Rad54 knockout in the DT40 chicken cells. The combination treatments of cisplatin and radiation showed that inhibition of the HR repair pathway resulted in super additive effects while the inhibition of the NHEJ pathway in DT40 had no effect. In mouse cells the knockout of the NHEJ pathway resulted in reduced super additivity compared to the parental cell lines. These data show that radiation, cisplatin and combination treatment damage is affected differently by the various DNA repair pathways, which could have a range of effects on combination treatments in tumour cells expressing different levels of DNA repair in the various repair pathways.

Animals↗