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At least 289 records · Page 16Linked to original sources
PubMed2001

Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity on hematologic malignancies.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced both cytotoxic (apoptosis) and cytostatic (cell cycle perturbation) effects on the human myeloid K562 cell line. TRAIL stimulated caspase 3 and nitric oxide synthase (NOS) activities, and both pathways cooperate in mediating inhibition of K562 survival/growth. This was demonstrated by the ability of z-VAD-fmk, a broad inhibitor of effector caspases, and N-nitro-L-arginine methyl ester (L-NAME), an NOS pharmacologic inhibitor, to completely (z-VAD-fmk) or partially (L-NAME) suppress the TRAIL-mediated inhibitory activity. Moreover, z-VAD-fmk was able to block TRAIL-mediated apoptosis and cell cycle abnormalities and increase of NOS activity. The addition of the NO donor sodium nitroprusside (SNP) to K562 cells reproduced the cytostatic effect of TRAIL without inducing apoptosis. When TRAIL was associated to SNP, a synergistic increase of apoptosis and inhibition of clonogenic activity was observed in K562 cells as well as in other myeloblastic (HEL, HL-60), lymphoblastic (Jurkat, SupT1), and multiple myeloma (RPMI 8226) cell lines. Although SNP greatly augmented TRAIL-mediated antileukemic activity also on primary leukemic blasts, normal erythroid and granulocytic cells were less sensitive to the cytotoxicity mediated by TRAIL with or without SNP. These data indicate that TRAIL promotes cytotoxicity in leukemic cells by activating effector caspases, which directly lead to apoptosis and stimulate NO production, which mediates cell cycle abnormalities. Both mechanisms seem to be essential for TRAIL-mediated cytotoxicity.

Apoptosis↗
PubMed2006

Targeting the Hedgehog pathway in cancer.

Several key signalling pathways, such as Hedgehog, Notch, Wnt and BMP-TGFbeta-Activin (bone morphogenetic protein-transforming growth factor-beta-Activin), are involved in most processes essential to the proper development of an embryo. It is also becoming increasingly clear that these pathways can have a crucial role in tumorigenesis when reactivated in adult tissues through sporadic mutations or other mechanisms. We will focus here on the Hedgehog pathway, which is abnormally activated in most basal cell carcinomas, and discuss potential therapeutic opportunities offered by the progress made in understanding this signalling pathway.

Animals↗
PubMed2003

Association of T cell antigen CD7 with type II phosphatidylinositol-4 kinase, a key component in pathways of inositol phosphate turnover.

CD7 is a 40-kDa glycoprotein that is expressed on prothymocytes and persists during T cell differentiation. CD7 has been demonstrated to generate, like other costimulatory molecules, intracellular signals that modulate T cell function. However, although it binds to phosphatidylinositol 3-kinase (PI 3-kinase), the signaling events mediated by CD7 are not completely understood. In this context, phosphatidylinositol 4-kinase (PI 4-kinase) is a key enzyme involved in a variety of events, from the modeling of the actin cytoskeleton to the activation of protein kinase C. In this study, we show for the first time that PI 4-kinase of 55 kDa can associate with CD7. The enzyme activity was insensitive to wortmannin, but was inhibited by adenosine, a characteristic for type II PI 4-kinase. Together, our findings demonstrate that type II PI 4-kinases are integral components of the CD7 signaling pathway and may play a role of CD7 in co-stimulation and thymic differentiation.

1-Phosphatidylinositol 4-Kinase↗
PubMed2005

Nicotinamide homeostasis: a xenobiotic pathway that is key to development and degenerative diseases.

Monkeys and man are very closely related genetically. Yet intellectually there are big differences and they suffer from a broad range of different diseases. For example, monkeys do not get Parkinson's or Alzheimer's disease. The former is surprising given that both get parkinsonism from MPTP poisoning and the latter initially less surprising as the cortex predominantly affected in Alzheimer's never developed as fully in the monkey. Man is an omnivore whilst other primates are predominantly herbivores. The one primate who was almost wholly carnivorous was Neanderthal man who became extinct. Red meat has a high content of Nicotinamide, Choline, and methyl donors. The enzyme NNMT converts nicotinamide to N-methyl-nicotinamide using SAM as the methyl donor. It is not present to any degree in herbivores. It has recently been shown to be present in human brain and up regulated in Parkinson's disease. Omnivores presumably need it for nicotinamide homeostasis but the production of N-methyl-nicotinamide will also be beneficial as it will reduce the export of Choline from neurones. Both will aid brain growth and development. However, as N-methyl-nicotinamide resembles MPTP it could cause parkinsonism later in life for man but not monkeys as they would be predicted not to have as much NNMT. Humans with a diet low in Nicotinamide,Choline or methyl donors early in life and low enzyme activity may be prone to Alzheimer's as their brain and therefore its reserves may never have developed as fully. The possession of NNMT plus a diet rich in Nicotinamide, Choline and methyl providers may explain many of the advantages but also the disadvantages of the human condition. One prediction is that a diet rich in these micronutrients whilst young will improve brain development and reduce the risk of Alzheimer's but that a lower dose later in life will reduce the risk of Parkinsonism. A second prediction is that it will become clear that dietary factors including vitamins are signalers and at the head of vital biochemical pathways. A time point will be reached when errors emerge that could not be deleted by evolutionary pressures. Finding and rectifying them will be the key to preventing many common diseases.

Animals↗
PubMed2005

JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species.

c-Jun N-terminal kinase (JNK), or stress-activated protein kinase, is an important member of the mitogen-activated protein kinase superfamily, the members of which are readily activated by many environmental stimuli. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important groups of free radicals that are capable of eliciting direct damaging effects or acting as critical intermediate signaling molecules, leading to oxidative and nitrosative stress and a series of biological consequences. Recently there has been an increasing amount of research interest focusing on the regulatory role of JNK activation in ROS-and RNS-induced cellular responses. In this review we will first summarize and discuss some recent findings regarding the signaling mechanisms of ROS-or RNS-mediated JNK activation. Second, we will talk about the role of JNK in ROS-or RNS-mediated cell death (both apoptosis and necrosis). Finally, we will analyze the emerging evidence for the involvement of ROS and RNS as mediators in tumor necrosis factor alpha-induced apoptosis. Taken together, the accumulating knowledge about the ROS/RNS-induced JNK signaling pathway has greatly advanced our understanding of the complex processes deciding the cellular responses to environmental stress.

Animals↗
PubMed2001

The IKK-2/Ikappa Balpha /NF-kappa B pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts. A critical link to dermatitis in Ikappa Balpha -deficient mice.

Tumor necrosis factor (TNF)-alpha-induced phosphorylation of the IkappaB proteins by the IkappaB kinase (IKK) complex containing IKK-2 and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation, resulting in the stimulation of a variety of pro-inflammatory target genes. The C-C chemokine eotaxin-1 is a potent chemoattractant for eosinophils and Th2 lymphocytes, may play an important role in the pathogenesis of atopic dermatitis, and acts via binding to its receptor CCR3. To investigate the role of NF-kappaB signaling in the regulation of these genes, we stably expressed a transdominant mutant of IkappaBalpha and a constitutively active mutant of IKK-2 in mouse NIH3T3 fibroblasts. The transdominant IkappaBalpha mutant completely inhibited TNF-alpha-mediated induction of both eotaxin-1 and CCR3, whereas expression of constitutively active IKK-2 was sufficient to drive almost full expression of these two genes in the absence of TNF-alpha. Moreover, we observed elevated expression levels of CCR3 and eotaxin-1 protein levels in the skin of IkappaBalpha-deficient mice characterized by a widespread dermatitis. Finally, using dermal fibroblasts derived from IkappaBalpha-deficient mice, we observed elevated basal expression, enhanced inducibility by TNF-alpha, and attenuated down-regulation upon TNF-alpha withdrawal of both CCR3 and eotaxin-1 mRNA levels. These results demonstrate that the IKK-2/IkappaBalpha/NF-kappaB pathway plays a critical role for CCR3 and eotaxin-1 expression in fibroblasts and suggests a critical link to the pathogenesis of atopic dermatitis.

3T3 Cells↗
PubMed2000

Molecular evolution of apoptotic pathways: cloning of key domains from sponges (Bcl-2 homology domains and death domains) and their phylogenetic relationships.

Cells from metazoan organisms are eliminated in a variety of physiological and pathophysiological processes by apoptosis. In this report, we describe the cloning and characterization of molecules from the marine sponges Geodia cydonium and Suberites domuncula, whose domains show a high similarity to those that are found in molecules of the vertebrate Bcl-2 superfamily and of the death receptors. The Bcl-2 proteins contain up to four Bcl-2 homology regions (BH). Two Bcl-2-related molecules have been identified from sponges that are provided with two of those regions, BH1 and BH2, and are termed Bcl-2 homology proteins (BHP). The G. cydonium molecule, BHP1_GC, has a putative size of 28,164, while the related sequence from S. domuncula, BHP1_SD, has a M(r) of 24,187. Phylogenetic analyses of the entire two sponge BHPs revealed a high similarity to members of the mammalian Bcl-2 superfamilies and to the Caenorhabditis elegans Ced-9. When the two domains, BH1 and BH2, are analyzed separately, again the highest similarity was found to the members of the Bcl-2 superfamily, but a clearly lower relationship to the C. elegans BH1 and BH2 domains in Ced-9. In unrooted phylogenetic trees the sponge BH1 and BH2 are grouped among the mammalian sequences and are only distantly related to the C. elegans BH domains. The analysis of the gene structure of the G. cydonium BHP showed that the single intron present is located within the BH2 domain at the same position as in C. elegans and rat Bcl-x(L). In addition, a sponge molecule comprising two death domains has been characterized from G. cydonium. The two death domains of the potential proapoptotic molecule GC_DD2, M(r) 24,970, share a high similarity with the Fas-FADD/MORT1 domains. A death domain-containing molecule has not been identified in the C. elegans genome. The phylogenetic analysis revealed that the sponge domain originated from an ankyrin building block from which the mammalian Fas-FADD/MORT1 evolved. It is suggested that the apoptotic pathways that involve members of the Bcl-2 superfamily and of the death receptors are already present in the lowest metazoan phylum, the Porifera.

Amino Acid Sequence↗
PubMed2005

Resveratrol inhibits type II phosphatidylinositol 4-kinase: a key component in pathways of phosphoinositide turn over.

Resveratrol has anti-inflammatory, cardio protective and cancer chemopreventive properties. The molecular targets for resveratrol in early signaling cascades are not well understood. Resveratrol inhibits type II PtdIns 4-kinase but not PtdIns 3-kinase activity in vitro. Resveratrol directly binds to the enzyme with a Kd of 7.2 microM. Kinetic studies show that resveratrol competes with PtdIns binding. Inhibition of PtdIns 4-kinase activity by resveratrol/phenylarsine oxide reduces Jurkat cell adhesion to matrigel/fibronectin coated surfaces, suggesting a role for type II PtdIns 4-kinase in lymphocyte infiltration to the sites of inflammation.

1-Phosphatidylinositol 4-Kinase↗
PubMed2004

Signalling in T-lymphocyte development: integration of signalling pathways is the key.

alpha beta T-cell development is restricted to the thymus. Interactions between developing lymphocytes and the thymic stroma, together with bone-marrow-derived monocytes and dendritic cells, are critical for proper development of the T-cell lineage. The developmental sequence through which T-cell progenitors pass on their way to maturity is well established, and can be followed by the sequential acquisition and/or removal of cell surface molecules. Using the combination of modern genetic manipulations, such as transgenesis, gene ablation (knockouts) and targeted mutagenesis (knock-ins), with the ever-improving conditional and inducible manipulation of gene expression, we are beginning to gain an understanding of how intercellular interactions can be relayed via intracellular signalling cascades to bring about nuclear re-organisation and the differentiated mature CD4(+) and CD8(+) subpopulations.

Animals↗
PubMed2005

The involvement of key DNA repair pathways in the formation of chromosome rearrangements in embryonic stem cells.

It is vital that embryonic stem (ES) cells, which give rise to the diverse tissues of the mature organism, maintain genetic stability. To understand mechanisms for the prevention and causation of chromosomal instability, we have used spectral karyotyping (SKY) to analyse ES cells from wild-type and repair-gene knockout mice. We chose cells deficient in Ku70 (DNA end joining), Xrcc2 (gene conversion), Ercc1 (single-strand annealing) and Csb (transcription-coupled repair) to represent potentially-important DNA repair pathways, plus an Xpc-deficient line to examine loss of global nucleotide excision repair (NER). Spontaneous and radiation (X-ray or alpha-particle)-induced chromosome changes were assessed to measure the influence of different levels of damage severity on response. We show that most repair pathways (except for global NER) protect against chromosome changes induced by ionizing radiations, while only homology-dependent pathways protect against spontaneous chromosomal change in ES cells. However, for a given level of damage, the prevalence of different types of changes alters in the different repair-deficient lines. Thus, loss of Ercc1, Csb or Ku70 leads to increased fragment formation, but loss of Xrcc2 promotes exchanges between chromosomes. Strikingly, we found that loss of the Csb gene function specifically protects ES cells from complex exchanges, suggesting a role for transcription-associated events in complex exchange formation.

Animals↗
PubMed2005

AMP-activated protein kinase: a key stress signaling pathway in the heart.

AMP-activated protein kinase (AMPK) is activated during exercise and ischemia and is emerging as an important regulatory mechanism in the heart. AMPK promotes adenosine triphosphate-generating pathways, including glucose transport, glycolysis, and fatty acid oxidation, while inhibiting energy-consuming anabolic pathways. After ischemia-reperfusion, AMPK-deficient hearts from transgenic mice have severe left ventricular contractile dysfunction with increased apoptosis and necrosis. Mutations in the AMPKgamma(2) subunit lead to cardiac glycogen overload, Wolff-Parkinson-White syndrome, arrhythmias, and heart failure. This review focuses on the molecular mechanisms of activation and cardiovascular actions of AMPK in the heart.

AMP-Activated Protein Kinases↗
PubMed2004

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca2+ entry pathway.

At central synapses, P/Q-type Ca(2+) channels normally provide a critical Ca(2+) entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking alpha(1A) (Ca(V)2.1), the pore-forming subunit of P/Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from alpha(1A) (-/-) mice. First, the presynaptic response to an ionophore-mediated Ca(2+) elevation was 50% greater, indicating an enhanced Ca(2+) sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in alpha(1A) (-/-) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in alpha(1A) (-/-) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the alpha(1A) (-/-) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca(2+)-sensing molecules were consistent with implications of the direct physiological experiments.

Animals↗
PubMed2003

Hypothalamic digoxin, cerebral chemical dominance, and pathogenesis of pulmonary diseases.

The isoprenoid pathway is a key regulatory pathway in the cell. It synthesizes digoxin, an endogenous membrane Na(+)-K+ ATPase inhibitor and modulator of synaptic transmission. The role of the isoprenoid pathway in lung diseases and its relation to hemispheric dominance was assessed in this study. The following parameters were measured in patients with (i) bronchial asthma, (ii) chronic bronchitis emphysemia, (iii) idiopathic pulmonary fibrosis, (iv) sarcoidosis, and (v) in individuals with right hemispheric, left hemispheric and bihemispheric dominance: 1. plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels, 2. tryptophan, tyrosine catabolic patterns, 3. free radical metabolism, 4. glycoconjugate metabolism, and 5. membrane composition. In patients with lung disease there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. The RBC membrane Na(+)-K+ ATPase activity and serum magnesium were decreased. There was also an increase in tryptophan catabolites and reduction in tyrosine catabolites in the serum. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these patients. The same biochemical patterns were obtained in individuals with right hemispheric chemical dominance. An upregulated isoprenoid pathway and hyperdigoxinemia are characteristic of lung disease and right hemispheric chemical dominance. Right hemispheric chemical dominance is important in deciding the predisposition to lung disease.

Adult↗
PubMed2006

Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: a link between a key cell proliferative pathway and membrane synthesis.

Akt is a critical regulator of cell growth, proliferation, and survival that is activated by phosphatidylinositol 3-kinase (PI3K). We investigated the effect of PI3K inhibition on activation of sterol regulatory element binding protein-2 (SREBP-2), a master regulator of cholesterol homeostasis. SREBP-2 processing increased in response to various cholesterol depletion approaches (including statin treatment) and this increase was blunted by treatment with a potent and specific inhibitor of PI3K, LY294002, or when a plasmid encoding a dominant-negative form of Akt (DN-Akt) was expressed. LY294002 also suppressed SREBP-2 processing induced by insulin-like growth factor-1. Furthermore, LY294002 treatment down-regulated SREBP-2 or -1c gene targets and decreased cholesterol and fatty acid synthesis. Fluorescence microscopy studies indicated that LY294002 disrupts transport of the SREBP escort protein, SCAP, from the endoplasmic reticulum to the Golgi. This disruption was also shown by immunofluorescence staining when DN-Akt was expressed. Taken together, our studies indicate that the PI3K/Akt pathway is involved in SREBP-2 transport to the Golgi, contributing to the control of SREBP-2 activation. Our results provide a crucial mechanistic link between the SREBP and PI3K/Akt pathways that may be reconciled teleologically because synthesis of new membrane is an absolute requirement for cell growth and proliferation.

Animals↗
PubMed2004

Mitochondria-dependent pathway is involved in heat-induced male germ cell death: lessons from mutant mice.

The signaling events leading to apoptosis can be divided into two major pathways, involving either mitochondria (intrinsic) or death receptors (extrinsic). In a recent study, we have shown the involvement of the mitochondria-dependent apoptotic pathway in heat-induced male germ cell apoptosis in the rat. In additional studies, using the gld (generalized lymphoproliferation disease) and lprcg (lymphoproliferation complementing gld) mice, which harbor loss-of-function mutations in Fas L and Fas, respectively, we have shown that heat-induced germ cell apoptosis is not blocked, thus providing evidence that the Fas signaling system is not required for heat-induced germ cell apoptosis in the testis. In the present study, we have found that the initiation of apoptosis in wild-type mice was preceded by a redistribution of Bax from a cytoplasmic to paranuclear localization in heat-susceptible germ cells. The relocation of Bax is accompanied by sequestration of ultracondensed mitochondria into paranuclear areas of apoptotic germ cells, cytosolic translocation of mitochondrial cytochrome c and DIABLO, and is associated with activation of the initiator caspase 9 and the executioner caspase 3. Similar events were also noted in both gld and lprcg mice. Taken together, these results indicate that the mitochondria-dependent pathway is the key apoptotic pathway for heat-induced male germ cell death in mice.

Animals↗
PubMed2006

Key inflammatory signaling pathways are regulated by the proteasome.

Lipopolysaccharide (LPS) is a major structural component of all Gram-negative organisms and has been implicated in Gram-negative sepsis and septic shock. In the present study, Affymetrix microarray analysis of RNA derived from murine macrophages treated with LPS in the absence or presence of the proteasome inhibitor lactacystin revealed that the vast majority of genes regulated by LPS is under control of the proteasome. Analysis of the data has revealed that the products of these genes participate in 14 distinct signaling pathways. This represents a novel approach to the identification of signaling pathways that are both toll-like receptor 4- and proteasome-dependent and may lead to the development of new drug targets in Gram-negative sepsis and septic shock.

Acetylcysteine↗
PubMed2006

Characterization of the beta-ketoadipate pathway in Sinorhizobium meliloti.

Aromatic compounds represent an important source of energy for soil-dwelling organisms. The beta-ketoadipate pathway is a key metabolic pathway involved in the catabolism of the aromatic compounds protocatechuate and catechol, and here we show through enzymatic analysis and mutant analysis that genes required for growth and catabolism of protocatechuate in the soil-dwelling bacterium Sinorhizobium meliloti are organized on the pSymB megaplasmid in two transcriptional units designated pcaDCHGB and pcaIJF. The pcaD promoter was mapped by primer extension, and expression from this promoter is demonstrated to be regulated by the LysR-type protein PcaQ. Beta-ketoadipate succinyl-coenzyme A (CoA) transferase activity in S. meliloti was shown to be encoded by SMb20587 and SMb20588, and these genes have been renamed pcaI and pcaJ, respectively. These genes are organized in an operon with a putative beta-ketoadipyl-CoA thiolase gene (pcaF), and expression of the pcaIJF operon is shown to be regulated by an IclR-type transcriptional regulator, SMb20586, which we have named pcaR. We show that pcaR transcription is negatively autoregulated and that PcaR is a positive regulator of pcaIJF expression and is required for growth of S. meliloti on protocatechuate as the carbon source. The characterization of the protocatechuate catabolic pathway in S. meliloti offers an opportunity for comparison with related species, including Agrobacterium tumefaciens. Differences observed between S. meliloti and A. tumefaciens pcaIJ offer the first evidence of pca genes that may have been acquired after speciation in these closely related species.

Adipates↗