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At least 469 records · Page 26Linked to original sources
PubMed2003

Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells.

A number of studies have demonstrated that the STAT pathway is an important signaling cascade utilized by the IL-6 cytokine family to regulate a variety of cell functions. However, the downstream target genes of STAT activation that mediate the cytokine-induced cellular responses are largely uncharacterized. The aims of the current study are to determine whether the STAT signaling pathway is critically involved in the oncostatin M (OM)-induced growth inhibition and morphological changes of MCF-7 cells and to identify STAT3-target genes that are utilized by OM to regulate cell growth and morphology. We show that expression of a dominant negative (DN) mutant of STAT3 in MCF-7 cells completely eliminated the antiproliferative activity of OM, whereas expression of DN STAT1 had no effect. The growth inhibition of breast cancer cells was achieved through a concerted action of OM on cell cycle components. We have identified four cell cycle regulators including c-myc, cyclin D1, c/EBPdelta, and p53 as downstream effectors of the OM-activated STAT3 signaling cascade. The expression of these genes is differentially regulated by OM in MCF-7 cells, but is unaffected by OM in MCF-7-dnStat3 stable clones. We also demonstrate that the OM-induced morphological changes are correlated with increased cell motility in a STAT3-dependent manner. Expression analysis of extracellular matrix (ECM) proteins leads to the identification of fibronectin as a novel OM-regulated ECM component. Our studies further reveal that STAT3 plays a key role in the robust induction of fibronectin expression by OM in MCF-7 and T47D cells. These new findings provide a molecular basis for the mechanistic understanding of the effects of OM on cell growth and migration.

Breast Neoplasms↗
PubMed2003

17alpha-estradiol-induced VEGF-A expression in rat pituitary tumor cells is mediated through ER independent but PI3K-Akt dependent signaling pathway.

17alpha-E(2), a weak estrogen exhibited both agonistic and antagonistic effects, and caused a time- and dose-dependent induction of VEGF-A mRNA expression in GH3 rat pituitary tumor cells. This effect was unaffected by the presence of the pure estrogen receptor antagonist ICI 182,780 but was specifically blocked by a protein synthesis inhibitor puromycin. Inhibition of phosphatidylinositol-3 kinase (PI3K) activity by wortmannin decreased the effect of 17alpha-E(2) on VEGF-A mRNA expression. This inhibitor also blocked the increase in phosphorylation of Akt induced by exposure to 17alpha-E(2). In contrast, exposure to the MAP kinase inhibitor, U0126, had no impact on 17alpha-E(2)-induced VEGF-A mRNA expression. Taken together, these studies indicate that like potent estrogens 17alpha-E(2) up-regulates VEGF-A mRNA expression in estrogen responsive GH3 rat pituitary tumor cells, but this induction is not mediated through a classical estrogen receptor pathway. PI3K-Akt signaling pathway is required for the induction of VEGF-A mRNA in GH3 cells by 17alpha-E(2).

Androstadienes↗
PubMed2005

Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: molecular targets are TBK1 and RIP1 in TRIF complex.

TLRs can activate two distinct branches of downstream signaling pathways. MyD88 and Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) pathways lead to the expression of proinflammatory cytokines and type I IFN genes, respectively. Numerous reports have demonstrated that resveratrol, a phytoalexin with anti-inflammatory effects, inhibits NF-kappaB activation and other downstream signaling pathways leading to the suppression of target gene expression. However, the direct targets of resveratrol have not been identified. In this study, we attempted to identify the molecular target for resveratrol in TLR-mediated signaling pathways. Resveratrol suppressed NF-kappaB activation and cyclooxygenase-2 expression in RAW264.7 cells following TLR3 and TLR4 stimulation, but not TLR2 or TLR9. Further, resveratrol inhibited NF-kappaB activation induced by TRIF, but not by MyD88. The activation of IFN regulatory factor 3 and the expression of IFN-beta induced by LPS, poly(I:C), or TRIF were also suppressed by resveratrol. The suppressive effect of resveratrol on LPS-induced NF-kappaB activation was abolished in TRIF-deficient mouse embryonic fibroblasts, whereas LPS-induced degradation of IkappaBalpha and expression of cyclooxygenase-2 and inducible NO synthase were still inhibited in MyD88-deficient macrophages. Furthermore, resveratrol inhibited the kinase activity of TANK-binding kinase 1 and the NF-kappaB activation induced by RIP1 in RAW264.7 cells. Together, these results demonstrate that resveratrol specifically inhibits TRIF signaling in the TLR3 and TLR4 pathway by targeting TANK-binding kinase 1 and RIP1 in TRIF complex. The results raise the possibility that certain dietary phytochemicals can modulate TLR-derived signaling and inflammatory target gene expression and can alter susceptibility to microbial infection and chronic inflammatory diseases.

Adaptor Proteins, Signal Transducing↗
PubMed2004

ORF36 protein kinase of Kaposi's sarcoma herpesvirus activates the c-Jun N-terminal kinase signaling pathway.

alpha-, beta-, and gamma-Herpesviruses encode putative viral protein kinases. The herpes simplex virus UL13, varicella-zoster virus ORF47, and Epstein-Barr virus BGLF4 genes all show protein kinase domains in their protein sequences. Mutational analysis of these herpesviruses demonstrated that the viral kinase is important for optimal virus growth. Previous studies have shown that ORF36 of Kaposi's sarcoma herpesvirus (KSHV) has protein kinase activity and is autophosphorylated on serine. The gene for ORF36 is expressed during lytic growth of the virus and has been classified as a late gene. Inspection of the ORF36 sequence indicated potential motifs that could be involved in activation of cellular transcription factors. To analyze the function of ORF36, the cDNA for this viral gene was tagged with the FLAG epitope and inserted into an expression vector for mammalian cells. Transfection experiments in 293T and SLK cells demonstrated that expression of ORF36 resulted in phosphorylation of the c-Jun N-terminal kinase. Autophosphorylation of ORF36 is important for JNK activation because a mutation in the predicted catalytic domain of ORF36 blocked its ability to phosphorylate JNK. Western blot analysis, using phosphospecific antibodies, revealed that mitogen-activated kinases MKK4 and MKK7 were phosphorylated by ORF36 but not by the kinase-negative mutant. Binding experiments in transfected cells also demonstrated that both the wild type and kinase-negative mutant of ORF36 form a complex with JNK, MKK4, and MKK7. In addition, using a tetracycline-inducible Rta BCBL-1 cell line (TREx BCBL1-Rta), JNK was phosphorylated during lytic replication, and inhibition of JNK activation blocked late viral gene expression but not early viral gene expression. In summary, these studies demonstrate that KSHV ORF36 activates the JNK pathway; thus this cell signaling pathway may function in the KSHV life cycle by regulating viral and/or cellular transcription.

Blotting, Western↗
PubMedDate not supplied

JNK and ERK signaling pathways in multistage mouse carcinogenesis: studies in the inhibition of signaling cascades as a means to understand their in vivo biological role.

Amplification and mutation of Ha-ras has been shown to correlate with the malignancy of tumors that appear in chemically-induced mouse skin. Cell lines isolated from mouse skin tumors represent the evolutionary stages of tumor development. Due to the high Ha-ras levels the JNK and ERK modules are found elevated, contributing to the enhanced AP-1 activity in the more malignant cells. To examine the role of the transforming Ha-ras in controlling ERK signaling, transfection of an activated Ha-ras allele was tested in a squamous cell carcinoma cell line. The ERK1/2 signaling pathways were blocked pharmacologically by PD98059 MEK inhibitor, which inhibited cell proliferation and anchorage-independent growth of squamous and spindle carcinoma cells. In addition, treatment with PD98059 and introduction of the dominant negative ATF-2 mutant into the spindle carcinoma cells, partially reverted the spindle phenotype to squamous-like. These results suggest that ERK1/2 and A TF-2 play an important role in oncogenicity and in the degree of progression within the mouse skin carcinogenesis system.

Animals↗
PubMed2004

Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspases and suppression of the Akt-phosphatidylinositol 3'-kinase signaling pathway.

Although glucocorticoids are known to induce apoptosis in chondrocytes, the mechanisms for this effect and the potential antiapoptotic role of IGF-I are unknown. To address this, we studied the effects of dexamethasone (Dexa) on apoptosis in the HCS-2/8 chondrocytic cell line. Dexa (25 microm) increased apoptosis (cell death ELISA) by 39% and 45% after 48 and 72 h, respectively (P < 0.01 and P < 0.05, respectively). IGF-I (100 ng/ml) decreased Dexa-induced apoptosis to levels similar to control cells. Apoptosis was associated with cleavage of poly-ADP-ribose polymerase (PARP) and alpha-fodrin and activation of caspases-8, -9, and -3 (Western), an effect that was counteracted when chondrocytes were cocultured with Dexa + IGF-I. Inhibitors for caspases-8, -9, and -3 (50 microm each) equally suppressed Dexa-induced apoptosis (P < 0.01). Time-response experiments showed that caspase-8 was activated earlier (at 12 h) than caspase-9 (at 36 h). We studied the phosphatidylinositol 3'-kinase (PI3K) pathway to further investigate the mechanisms of Dexa-induced apoptosis. Dexa decreased Akt phosphorylation by 93% (P < 0.001) without affecting total Akt and increased the p85alpha subunit 4-fold. The Akt inhibitor SH-6 (10 microm) increased apoptosis by 54% (P < 0.001). When combining Dexa with SH-6, apoptosis was not further increased, showing that Dexa-induced apoptosis is mediated through inhibition of the PI3K pathway. Addition of IGF-I to SH-6- or Dexa + SH-6-treated cells decreased apoptosis by 21.2% (P < 0.001) and 20.6% (P < 0.001), respectively. We conclude that Dexa-induced apoptosis is caspase dependent with an early activation of caspase-8. IGF-I can rescue chondrocytes from Dexa-induced apoptosis partially through the activation of other pathways than the PI3K signaling pathway. Based on our in vitro data, we speculate that in vivo treatment with glucocorticoids may diminish longitudinal growth by increasing apoptosis of proliferative growth plate chondrocytes.

Apoptosis↗
PubMed2001

Monitoring of methyl jasmonate-responsive genes in Arabidopsis by cDNA macroarray: self-activation of jasmonic acid biosynthesis and crosstalk with other phytohormone signaling pathways.

Jasmonates mediate various physiological events in plant cells such as defense responses, flowering, and senescence through intracellular and intercellular signaling pathways, and the expression of a large number of genes appears to be regulated by jasmonates. In order to obtain information on the regulatory network of jasmonate-responsive genes (JRGs) in Arabidopsis thaliana (Arabidopsis), we screened 2880 cDNA clones for jasmonate responsiveness by a cDNA macroarray procedure. Since many of the JRGs reported so far have been identified in leaf tissues, the cDNA clones used were chosen from a non-redundant EST library that was prepared from above-ground organs. Hybridization to the filters was achieved using alpha-33P-labeled single-strand DNAs synthesized from mRNAs obtained from methyl jasmonate (MeJA)-treated and untreated Arabidopsis seedlings. Data analysis identified 41 JRGs whose mRNA levels were changed by more than three fold in response to MeJA. This was confirmed by Northern blot analysis by using eight representatives. Among the 41 JRGs identified, 5 genes were JA biosynthesis genes and 3 genes were involved in other signaling pathways (ethylene, auxin, and salicylic acid). These results suggest the existence of a positive feedback regulatory system for JA biosynthesis and the possibility of crosstalk between JA signaling and other signaling pathways.

Acetates↗
PubMed2004

The ethylene signaling pathway.

Plants use a structurally very simple gas molecule, the hydrocarbon ethylene, to modulate various developmental programs and coordinate responses to a multitude of external stress factors. How this simple molecule generates such a diverse array of effects has been the subject of intense research for the past two decades. A fascinating signaling pathway, with classical as well as novel plant-specific signaling elements, is emerging from these studies. We describe the four main modules that constitute this signaling pathway: a phosphotransfer relay, an EIN2-based unit, a ubiquitin-mediated protein degradation component, and a transcriptional cascade. The canonical and Arabidopsis ethylene signaling pathways in the Signal Transduction Knowledge Environment Connections Maps provide a complete panoramic view of these signaling events in plants.

Arabidopsis↗
PubMed2006

Two signaling pathways regulate the expression and secretion of a neuropeptide required for long-term facilitation in Aplysia.

Activation of several signaling pathways contributes to long-term synaptic plasticity, but how brief stimuli produce coordinated activation of these pathways is not understood. In Aplysia, the long-term facilitation (LTF) of sensory neuron synapses by 5-hydroxytryptamine (serotonin; 5-HT) requires the activation of several kinases, including mitogen-activated protein kinase (MAPK). The 5-HT-enhanced secretion of the sensory neuron-specific neuropeptide sensorin mediates the activation of MAPK. We find that stimulus-induced activation of two signaling pathways, phosphoinositide 3-kinase (PI3K) and type II protein kinase A (PKA), regulate sensorin secretion and responses. Treatment with 5-HT produces a rapid increase in sensorin synthesis, especially at varicosities, which precedes the secretion of sensorin. PI3K inhibitor and rapamycin block LTF and the rapid synthesis of sensorin at varicosities even in the absence of sensory neuron cell bodies. Secretion of the newly synthesized sensorin from the varicosities and activation of the autocrine responses of sensorin to produce LTF require type II PKA interaction with AKAPs (A-kinase anchoring proteins). Thus, long-term synaptic plasticity is produced when multiple signaling pathways that are important for regulating distinct cellular functions are activated in a specific sequence and recruit the secretion of a neuropeptide to activate additional critical pathways.

Animals↗
PubMed2007

Molecular profiles of mitogen activated protein kinase signaling pathways in orofacial development.

BACKGROUND: Formation of the mammalian orofacial region involves multiple signaling pathways regulating sequential expression of and interaction between molecular signals during embryogenesis. The present study examined the expression patterns of members of the MAPK family in developing murine orofacial tissue. METHODS: Total RNA was extracted from developing embryonic orofacial tissue during gestational days (GDs) 12-14 and used to prepare biotinylated cDNA probes, which were then denatured and hybridized to murine MAPK signaling pathways gene arrays. RESULTS: Expression of a number of genes involved in the (ERK1/2) cascade transiently increased in the embryonic orofacial tissue over the developmental period examined. Numerous members of the SAPK/JNK cascade were constitutively expressed in the tissue. Genes known to play a role in p38 MAPK signaling exhibited constitutive expression during orofacial development. Western blot analysis demonstrated that ERK2/1, p38, and SAPK/JNK kinases are present in embryonic orofacial tissue on each of GD 12, 13, and 14. By using phospho-specific antibodies, active ERK was shown to be temporally regulated during orofacial development. Minimal amounts of active p38 and active SAPK/JNK were detected in orofacial tissue during GDs 12-14. CONCLUSIONS: Our study documents specific expression patterns of genes coding for proteins belonging to the ERK1/2, p38, and SAPK/JNK MAPK families in embryonic orofacial tissue. We also demonstrate that active, phosphorylated forms of ERK1/2 only were detected in the embryonic tissue investigated, suggesting a more central role for members of this family in embryonic orofacial development.

Animals↗
PubMed1997

HDL3 binds to glycosylphosphatidylinositol-anchored proteins to activate signalling pathways.

Previous studies have indicated that in HepG2 cells HDL3-signalling involves glycosylphosphatidylinositol (GPI) anchored proteins. HDL3-binding to HepG2 cells was found to be enhanced by cellular preincubation with PI-PLC inhibitors and sensitive to a cellular preincubation with exogenous PI-PLC, suggesting that HDL3 binds directly on GPI-anchored proteins to initiate signaling. Moreover HDL3-binding was found to be partly inhibited by antibodies against the HDL-binding protein (AbHBP). HDL3, when binding to HepG2 cells, promoted the release in the culture medium of a 110 kDa protein that binds AbHBP, while a cellular preincubation with antibodies against the inositol-phosphoglycan (IPG) moiety of GPI-anchor (AbIPG), used to block lipolytic cleavage of the GPI-anchor, inhibits HDL3-induced release of the 110 kDa protein in the culture medium. In [3H]-PC prelabeled HepG2 cells, AbHBP were found to stimulate PC-hydrolysis and DAG generation within 5 min as did HDL3 stimulation. Cellular preincubation with AbIPG was found to inhibit only the HDL3-signal and not the AbHBP-signal, while a prior cellular pretreatment with PI-PLC from Bacillus cereus was found to inhibit the HDL3-and AbHBP-signal. Moreover cellular preincubation with AbHBP for 1 h at 37 degrees C was found to inhibit HDL3-signalling pathways. Our results suggest that in HepG2 cells a 110 kDa protein, which could be HBP, can be anchored to the membrane via GPI, and can function in HDL3-signalling pathways as binding sites.

Antibodies↗
PubMed2004

Coexpression of Cux-1 and Notch signaling pathway components during kidney development.

Cux-1 is the murine homologue of the Drosophila gene cut, which is required for cellular differentiation in several tissues, including the wing margin and Malpighian tubule. Mammalian cut proteins function as cell cycle-dependent transcriptional repressors in proliferating cells. Targets of Cux-1 repression include the cyclin kinase inhibitors p21 and p27. However, little is known about the regulation of Cux-1. In Drosophila, multiple genetic interactions between Cut and the Notch and Wingless signaling pathways occur during wing development. To begin to determine whether Cux-1 regulation by the Notch signaling pathway is conserved in mammals, we compared the expression patterns of Cux-1, the murine Notch receptors (Notch 1-4), and the murine ligands (Jagged 1, Jagged 2, and Delta 1) during murine embryogenesis and kidney development. In this report, we demonstrate that Cux-1 expression overlaps with that of Notch signaling pathway components in multiple tissues during embryonic development. In the developing kidney, Cux-1 expression overlaps with that of Notch pathway components in the condensing mesenchyme, in pretubular aggregates (comma and S-shaped bodies), and in the presumptive podocytes of capillary loop stage glomeruli. Furthermore, Cux-1 was significantly up-regulated in the rat kidney epithelial cell line RKE expressing a constitutively active Notch 1, and this finding was associated with a reduction of p27. Moreover, Cux-1 interacts with the Groucho homolog TLE-4, a corepressor recruited by Notch effector proteins. Taken together, these results suggest that Cux-1 may function in the context of the Notch signaling pathway in multiple tissues during mammalian embryogenesis.

Animals↗
PubMed1994

A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways.

Transfection of NIH3T3 cells with an osteosarcoma expression cDNA library led to the appearance of foci of morphologically transformed cells which were found to harbor a novel oncogene, ost. The ost product was activated by truncation of the N-terminal domain of the ost proto-oncogene and was highly tumorigenic in nude mouse assays. The proto-ost cDNA, isolated subsequently, encodes a predicted protein of 100 kDa containing DH (Db1 homology) and PH (pleckstrin homology) domains. Ost is mainly phosphorylated on serine and localized in the cytoplasm. Purified Ost protein catalyzed guanine nucleotide exchange on RhoA and Cdc42 among the Rho and Ras family members tested, indicating that Ost can activate these small GTP-binding proteins. Ost did not detectably associate with RhoA or Cdc42, but interacted specifically with the GTP-bound form of Rac1, suggesting that Ost can function as an effector of Rac1. These results suggest that Ost is a critical regulatory component which links pathways that signal through Rac1, RhoA and Cdc42. Of the tissues examined, expression of ost was the highest in brain and could be localized to neurons and alpha-tanycytes, suggesting that Ost may participate in axonal transport in these specialized cells.

3T3 Cells↗
PubMed2006

The signaling pathway in histidine kinase and the response regulator complex revealed by X-ray crystallography and solution scattering.

The structure of a histidine kinase (ThkA) complexed with a response regulator (TrrA) in the two-component regulatory system from hyperthermophile Thermotoga maritima was determined by a combination of X-ray crystallography at a resolution of 4.2 A and small-angle X-ray scattering (SAXS). The boundary of the three component domains (PAS-sensor, dimerization and catalytic domains) of ThkA and the bound TrrA molecule were unambiguously assigned in the electron density map at 4.2 A resolution. ThkA forms a dimer with crystallographic 2-fold symmetry and two monomeric TrrAs bind to the ThkA dimer. SAXS experiments also confirmed this association state in solution and specific binding between ThkA and TrrA (Kd=8.2x10(-11) M(-2)). The association interface between ThkA and TrrA contains the phosphotransfer His residue in the ThkA, indicative of an efficient receipt of the phosphoryl group. One Per-Arnt-Sim (PAS) domain does not interact with the other PAS domain, but with the catalytic domain of the same polypeptide chain and with one TrrA molecule. Observed inter-domain and inter-molecular interactions reveal a definite pathway of signal transduction in the kinase/regulator complex. In addition, we propose a responsible role of TrrA for the feedback regulation of sensing and/or kinase activities of ThkA.

Amino Acid Sequence↗
PubMed2002

A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus.

In the present study we examined involvement of nuclear protein tyrosine phosphatase TC-PTP in PRL-mediated signaling. TC-PTP could dephosphorylate signal transducer and activator of transcription 5a (STAT5a) and STAT5b, but the apparent dephosphorylation activity of TC-PTP was weaker than that of cytosolic PTP1B 30 min after PRL stimulation in transfected COS-7 cells, whereas both STAT5a and STAT5b were dephosphorylated to the same extent by recombinant TC-PTP and PTP1B in vitro. Tyrosine-phosphorylated STAT5 was coimmunoprecipitated with substrate trapping mutants of TC-PTP, suggesting that STAT5 is a specific substrate of TC-PTP. These observations were further extended in mammary epithelial COMMA-1D cells stably expressing TC-PTP. A time-course study revealed that dephosphorylation of STAT5 by TC-PTP was delayed compared with that by cytosolic PTP1B due to nuclear localization of TC-PTP throughout PRL stimulation in mammary epithelial cells. Endogenous beta-casein gene expression and beta-casein gene promoter activation in COS-7 cells were largely suppressed by TC-PTP wild type as well as catalytically inactive mutants, suggesting that stable complexes formed between STAT5 and TC-PTP in the nucleus. Taken together, we conclude that TC-PTP is catalytically competent with respect to dephosphorylation and deactivation of PRL-activated STAT5 in the nucleus.

Animals↗
PubMed1996

The role of intracellular signalling pathways regulating thymocyte and leukemic T cell apoptosis.

Apoptosis plays a critical role during T cell development, both in the generation of functionally competent T cells in the thymus and the regulation of peripheral T cell populations. The fate of any T cell, whether it is developing in the thymus, or functioning in the peripheral immune system, is dependent on T cell receptor (TCR) specificity for antigens presented by MHC molecules and on the consequences of TCR-generated intracellular signalling pathways which lead to activation, anergy or apoptosis. This review describes data that have elucidated the way in which these highly regulated TCR-derived signalling pathways lead to such diverse final outcomes in thymocytes. Contributions to the induction of apoptosis in thymocytes by signalling pathways and receptors such as Fas, CD45 and CD28 are summarized, particularly with regard to the analysis of relevant transgenic mice. Developments concerning regulation of apoptosis by bcl-2 family members and the possible effectors of apoptosis, proteases, are assessed. Finally, this information is contrasted with the relatively scarce data on signalling pathways in thymic-derived T-ALL cells together with potential explanations of how transformation might occur by perturbation of apoptotic mechanisms. Precise understanding of these pathways may lead to the development of novel therapeutic reagents.

Animals↗
PubMed2000

Evidence for multiple signaling pathways in the regulation of gene expression by amino acids in human cell lines.

In mammals, plasma concentrations of amino acids (AA) are affected by nutritional or pathologic conditions. Alterations in AA profiles have been reported as a result of a deficiency of any one of the essential AA, a dietary imbalance of AA or an insufficient intake of protein. In recent years, evidence has accumulated that AA availability regulates the expression of several genes involved in the regulation of a number of cellular functions or AA metabolism. Nevertheless, the molecular mechanisms involved in the AA regulation of mammalian gene expression are limited, particularly the signaling pathways mediating the AA response. This work provides a better understanding of the signaling pathways involved in the AA control of gene expression. We studied the expression of C/EBP homologous protein (CHOP) and asparagine synthetase (AS) in response to deprivation of a single AA and investigated the possible link between protein synthesis inhibition due to amino acid limitation and gene expression. We have shown the following: 1) several mechanisms are involved in the AA control of gene expression. When omitted from the culture medium, each AA can activate one (or several) specific signaling pathways leading to the regulation of one specific pattern of genes. 2) AA limitation by itself can induce gene expression independently of a cellular stress due to protein synthesis inhibition. Together, these results suggest that AA control of gene expression involves several specific mechanisms by which one AA (or one group of AA) can activate one signaling pathway and thus alter one specific pattern of gene expression.

Amino Acids↗
PubMed2002

Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways.

BACKGROUND: Volatile anesthetics induce pharmacological preconditioning in cardiac tissue. The purpose of this study was to test whether volatile anesthetics mediate this effect by activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) or sarcolemmal K(ATP) (sarcK(ATP)) channel in rat ventricular myocytes and to evaluate the signaling pathways involved. METHODS: A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to determine the effects of 5-hydroxydecanoate, a selective mitoK(ATP) channel blocker, HMR-1098, a selective sarcK(ATP) channel blocker, diazoxide, a preconditioning mimicking agent, and various modulators of putative signaling pathways on cardioprotection elicited by sevoflurane and isoflurane. Microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct index of mitoK(ATP) channel activity. RESULTS: Volatile anesthetics significantly enhanced diazoxide-mediated activation of mitoK(ATP) channels as assessed by autofluorescence of myocytes. Conversely, volatile anesthetics alone did not alter mitoK(ATP) channel activity, implying a priming effect of volatile anesthetics on mitoK(ATP) channels. Administration of the protein kinase C inhibitor chelerythrine completely blocked this effect. Also, pretreatment with volatile anesthetics potentiated diazoxide-mediated protection against ischemia, as indicated by a reduction in trypan blue-positive myocytes. Importantly, cardioprotection afforded by volatile anesthetics was unaffected by the sarcK(ATP) channel blocker HMR-1098 but sensitive to modulations of nitric oxide and adenosine-G(i) signaling pathways. CONCLUSIONS: Using autofluorescence in live cell imaging microscopy and a simulated model of ischemia, the authors present evidence that volatile anesthetics mediate their protection in cardiomyocytes by selectively priming mitoK(ATP) channels through multiple triggering protein kinase C-coupled signaling pathways. These observations provide important new insight into the mechanisms of anesthetic-induced preconditioning.

Adenosine Triphosphate↗