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At least 757 records · Page 42Linked to original sources
PubMed2003

Caspase 8-mediated cleavage of the pro-apoptotic BCL-2 family member BID in p53-dependent apoptosis.

The objective of this study was to characterize the apoptotic pathways activated by fast neutrons in the human lymphoblastoid cell line TK6 and in its p53 -/- derivative. Our results demonstrate that while p53 is not required for neutron-induced apoptosis, as previously shown, it does affect the kinetics of apoptosis and the molecular pathways leading to the activation of effector caspases. Indeed, rapid p53-dependent apoptosis was associated with the activation of caspase 9, 8, 3, and 7 and the cleavage of BID by caspase 8. In contrast, the slow-occurring p53-independent apoptotic process, mediated by caspase 7, took place without BID cleavage and loss of transmembrane mitochondrial potential. Altogether, our findings highlight an essential role for caspase 8-mediated BID cleavage, in the course of p53-dependent apoptosis triggered by fast neutrons in lymphoid cells. They also demonstrate that this mechanism is not involved in p53-independent apoptosis.

Apoptosis↗
PubMed2002

Cancer genetics and their application to individualised medicine.

One of the great challenges of basic research is to translate scientific discoveries into the improved treatment of patients. For colorectal cancer, our increased understanding of the molecular aetiology of the disease has not yet been paralleled by an improvement in patient care. However, several new approaches are on the verge of clinical implementation. Technical advances such as real-time polymerase chain reaction (PCR) and microarray techniques coupled to insight in the molecular pathways in colorectal cancer makes it possible to develop new clinical tools for the diagnosis, classification and treatment of patients. The ultimate goal of the incorporation of cancer genetics into the clinical treatment of patients is individualised medicine; therapeutic strategies based on the molecular taxonomy of tumours and individually constructed for each patient.

Adenomatous Polyposis Coli↗
PubMed2006

The genomic analysis of the impact of steroid receptor coactivators ablation on hepatic metabolism.

Members of the steroid receptor coactivator (SRC) family, which include SRC-1 (NcoA-1/p160), SRC-2(TIF2/GRIP1/NcoA-2) and SRC-3(pCIP/RAC3/ACTR/pCIP/ AIB1/TRAM1), are critical mediators of steroid receptor action. Gene ablation studies previously identified SRC-1 and SRC-2 as being involved in the control of energy homeostasis. A more precise identification of the molecular pathways regulated by these coactivators is crucial for understanding the role of steroid receptor coactivators in the control of energy homeostasis and obesity. A genomic approach using microarray analysis was employed to identify the subsets of genes that are altered in the livers of SRC-1-/-, SRC-2-/-, and SRC-3-/- mice. Microarray analysis demonstrates that gene expression changes are specific and nonoverlapping for each SRC member in the liver. The overall pattern of altered gene expressions in the SRC-1-/- mice was up-regulation, whereas SRC-2-/- mice showed an overall down-regulation. Several key regulatory enzymes of energy metabolism were significantly altered in the liver of SRC-2-/- mice, which are consistent with the prior observation that SRC-2-/- mice have increased energy expenditure. This study demonstrates that the molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway, whereas fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated.

Animals↗
PubMed2005

Folate supplementation in three genetic models: implications for understanding folate-dependent developmental pathways.

Supplementation of a pregnant mother's diet with folate has been shown to protect the developing embryo from birth defects in humans as well as rodent animal models. Folate supplementation not only reverses a potential nutritional deficiency; folate effectively prevents defects even when the mother's nutritional status is normal. These findings indicate that folate is able to interact with the molecular pathways that control normal embryonic development. Supplementation studies in animals provide the experimental starting point for the identification of such folate-responsive pathways. This review summarizes the progress to date in understanding the folate response in genetic models of birth defects in the mouse.

Animals↗
PubMed2006

Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-alpha on this pathway.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-alpha in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-alpha in SLE patients' plasma.

Adult↗
PubMed1999

The relation of p53 gene mutations to gastric cancer subsite and phenotype.

OBJECTIVES: We investigated p53 gene mutations in advanced gastric cancers by direct DNA sequencing, in order to determine the frequency of mutations in gastric cancers having different epidemiological backgrounds, tumors of the cardia were compared with those arising in the antrum or corpus. Intestinal type cancers were compared with diffuse or other histologic types. We have chosen to assess the frequency of mutations solely based on DNA sequencing. METHODS: Paraffin embedded tissues from 100 gastric cancers were evaluated. The mutational status of the p53 gene in exons 5 through 9 were determined by direct sequencing of PCR products. RESULTS: Mutations in exons 5, 6, 7 and 8 were found in 35 of 100(35%)stomach cancers. One tumor had mutations in both exons 5 and 8. No mutations were detected in exon 9. p53 gene mutations were significantly more frequent in cancers of the cardia (19/35; 54%) than the antrum and corpus (16/65 (25%)) (p < or = 0.005). p53 mutations were more frequent in intestinal type cancers (28/67; 42%) than diffuse cancers or other histologic types of cancer (7/33; 21%), but the difference was not statistically significant. CONCLUSIONS: Cancers of the cardia more frequently contain p53 mutations than do antral and corpus cancers, suggesting that cancers in the proximal and distal stomach evolve through different molecular pathways.

Base Sequence↗
PubMed1998

Involvement of Sp1 elements in the promoter activity of the alpha1-proteinase inhibitor gene.

The transcripts of the alpha1-proteinase inhibitor in the cornea are different from those in hepatocytes and monocytes, suggesting that alpha1-proteinase inhibitor gene transcription may respond to different cell-specific regulatory mechanisms. Although information on alpha1-proteinase inhibitor gene structure has been obtained, little is known regarding the cis- and trans-acting factors that regulate its expression. In this study, we cloned and sequenced a 2. 7-kilobase 5'-flanking region upstream from the corneal transcription initiation site of the gene, demonstrated functional promoter activity, and identified the regulatory elements. Sequencing revealed that the 5'-flanking element was highly G/C-rich in regions proximal to the corneal transcription start site. DNase I footprinting located 10 potential Sp1-binding sites between nucleotides -1519 and +44. The putative promoter was functional in human corneal stromal cells, but not in human skin, scleral, and conjunctival fibroblasts, suggesting that the promoter may be corneal cell-specific. The promoter activity in the corneal cells was repressed when Sp1 was coexpressed. In the cornea-thinning disease keratoconus, down-regulation of the alpha1-proteinase inhibitor gene and increased Sp1 expression have both been demonstrated. The current results suggest that down-regulation of the inhibitor in keratoconus corneas may be related directly to overexpression of the Sp1 gene. This information may help elucidate the molecular pathways leading to the altered alpha1-proteinase inhibitor expression in keratoconus.

Base Sequence↗
PubMed2026

Evidence for dual pathways of Tc1/mariner domestication in Drosophila.

BACKGROUND: The domestication of transposable elements is a key source of evolutionary innovation, yet the pathways by which their functional modules are repurposed by the host remain poorly understood. The Tc1/mariner superfamily is a widespread group of DNA transposons, but the prevalence and patterns of their domestication are underexplored. RESULTS: We performed a systematic genomic screen across 43 drosophilid species using stringent criteria for molecular domestication. This analysis identified five high-confidence, evolutionarily conserved genes derived from Tc1/mariner transposases. Phylogenetic and structural analyses suggest domestication via two distinct molecular pathways: co-option of the DNA-binding module and co-option of the catalytic domain. The DNA-binding module pathway includes CG4570, the previously known genes cag and toy (the latter fused with a homeodomain), and a lineage-restricted gene in the Drosophila obscura group that exhibits signatures of recent domestication. In contrast, the catalytic domain pathway is represented solely by CG14478. Structural modeling reveals that CG14478 protein preserves a canonical DDE endonuclease fold. Co-expression network analysis suggests potential cellular roles of these genes: CG14478 is linked to RNA/chromatin-related processes, CG4570 to cell cycle/chromosome functions, cag to ciliary and nuclear functions, and toy to neuronal development. CONCLUSIONS: This study establishes a stringent framework for identifying domesticated TEs, demonstrating that Tc1/mariner elements are co-opted via two distinct pathways: retention of either catalytic or DNA-binding modules. Our findings suggest that domestication is a dynamic continuum, ranging from recent, lineage-specific events to ancient, conserved genes, and underscore how genomic conflict with TEs can drive eukaryotic evolution and regulatory complexity.

Animals↗
PubMed2006

Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization, which plays an important role in the growth and progression of HCC. Angiogenesis provides a target for novel prognostic and therapeutic approaches to HCC. Assessment of microvessel density using immunohistochemical staining for specific endothelial cell markers such as CD34 has been shown to provide prognostic information independent of conventional pathological parameters in HCC patients. Recent studies have unveiled the important angiogenic factors involved in the regulation of angiogenesis in HCC, although the exact molecular pathways are far from clear. Current data suggest that vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis of HCC. Tumor expression of VEGF has been shown to correlate with tumor invasiveness and prognosis in patients with HCC. VEGF is an important molecular target for antiangiogenic therapy. Studies in animal models have demonstrated the efficacy of antiangiogenic agents such as anti-VEGF antibody and antagonists of VEGF receptors in suppressing hepatocarcinogenesis and growth of HCC. Antiangiogenic therapy has already entered clinical trials in HCC patients and holds the promise of providing an effective novel treatment for HCC, which is of great clinical significance because there is no existing effective systemic therapy for HCC.

Angiogenesis Inhibitors↗
PubMed1999

Focal cortical dysplasia: a neuropathological and developmental perspective.

Focal cortical dysplasia (FCD) is a rare, sporadic disorder which is a recognised cause of chronic epilepsy. It is proposed to result from disordered neuronal migration and differentiation and has characteristic histological features which include disturbed cortical lamination, large abnormal neurons and the presence of large balloon cells with glassy eosinophilic cytoplasm and pleomorphic eccentric nuclei. These latter express both glial and neuronal markers indicative of abnormal neuroglial differentiation. In this paper we review the current literature on the neuropathology of FCD and discuss potential mechanisms. We focus on growth factors, signalling pathways and candidate genes with known roles in Drosophila and vertebrate brain development that could be responsible for the developmental brain changes seen in FCD. At issue are the factors that influence cell fate and differentiation and which regulate neural migration. Some of the molecular pathways, such as those involving the Notch and the Wnt pathways have particularly important roles in neuroglial differentiation in vertebrates, and these are proposed as potential candidates.

Animals↗
PubMed2001

Physiological function as regulation of large transcriptional programs: the cellular response to genotoxic stress.

The responses to ionizing radiation and other genotoxic environmental stresses are complex and are regulated by a number of overlapping molecular pathways. One such stress signaling pathway involves p53, which regulates the expression of over 100 genes already identified. It is also becoming increasingly apparent that the pattern of stress gene expression has some cell type specificity. It may be possible to exploit these differences in stress gene responsiveness as molecular markers through the use of a combined informatics and functional genomics approach. The techniques of microarray analysis potentially offer the opportunity to monitor changes in gene expression across the entire set of expressed genes in a cell or organism. As an initial step in the development of a functional genomics approach to stress gene analysis, we have recently demonstrated the utility of cDNA microarray hybridization to measure radiation-stress gene responses and identified a number of previously unknown radiation-regulated genes. The responses of some of these genes to DNA-damaging agents vary widely in cell lines from different tissues of origin and different genetic backgrounds. While this again highlights the importance of a cellular context to genotoxic stress responses, it also raises the prospect of expression-profiling of cell lines, tissues, and tumors. Such profiles may have a predictive value if they can define regions of 'expression space' that correlate with important endpoints, such as response to cancer therapy regimens, or identification of exposures to environmental toxins.

Animals↗
PubMed2003

Erythropoietin-induced serine 727 phosphorylation of STAT3 in erythroid cells is mediated by a MEK-, ERK-, and MSK1-dependent pathway.

OBJECTIVE: Erythropoietin (EPO) is a key regulator of erythropoiesis, playing a role in both the proliferation and differentiation of erythroid cells. One of the signal transduction molecules activated upon EPO stimulation is signal transducer and activator of transcription (STAT) 3. Besides tyrosine 705 phosphorylation of STAT3, serine 727 phosphorylation has been described upon EPO stimulation. In the present study, we investigated which molecular pathways mediate the STAT3 serine 727 phosphorylation and the functional implications of this phosphorylation. METHODS: The EPO-dependent erythroid cell line ASE2 was used to investigate which signaling routes were involved in the STAT3 serine 727 phosphorylation. Western blotting using phosphospecific antibodies was used to assess the phosphorylation status of STAT3 molecules. Transfection analysis was performed to investigate the transactivational potential of STAT3, and quantitative RT-PCR was used to study the in vivo gene expression of STAT3-responsive genes. RESULTS: Western blotting of extracts of cells exposed to various chemical inhibitors revealed that the MEK inhibitors PD98059 and U0126 abrogated the EPO-mediated STAT3 serine 727 phosphorylation without an effect on tyrosine phosphorylation. Further analysis showed that MSK1 is activated downstream of ERK, and retroviral transductions with kinase-inactive MSK1 revealed that MSK1 is necessary for STAT3 serine phosphorylation. Furthermore, the STAT3-mediated transactivation was reduced by blocking the STAT3 serine phosphorylation with the MEK inhibitor U0126 or by expression of kinase-inactive MSK1. CONCLUSIONS: The EPO-induced STAT3 serine 727 phosphorylation is mediated by a pathway involving MEK, ERK, and MSK1. Furthermore, serine phosphorylation of STAT3 augments the transactivational potential of STAT3.

Cell Line↗
PubMed2003

Interleukin-10 and the regulation of mitogen-activated protein kinases: are these signalling modules targets for the anti-inflammatory action of this cytokine?

The many specific, yet overlapping and redundant activities of individual cytokines have been the basis for current concepts of therapeutical intervention. Cytokines are powerful two-edged weapons that can trigger a cascade of reactions and may show activities that often go beyond the single highly specific property that it is hoped they possess. Nevertheless, it can be stated that our new, though burgeoning, understanding of the biological mechanisms governing cytokine actions is an important contribution to medical knowledge. The crucial role of the anti-inflammatory cytokine, interleukin (IL)-10, in regulating potential molecular pathway mediating injury and cell death has attracted paramount attention in recent years. In this respect, the mitogen-activated protein kinase (MAPK) components have emerged as potential signalling cascades that regulate a plethora of cell functions, including inflammation and cell death. The biochemistry and molecular biology of cytokine actions, particularly IL-10, explain some well known and sometimes also some of the more obscure clinical aspects of the evolution of diseases.

Animals↗
PubMed2006

Purkinje neuron degeneration in nervous (nr) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activator.

Purkinje neurons (PNs), the central cells in cerebellar circuitry and function, constitute a vulnerable population in many human genetic, malignant, hypoxic, and toxic diseases. In the nervous (nr) mutant mouse, the majority of PNs die in the fourth to fifth postnatal weeks, but the responsible molecules are unknown. We first disclose a remarkable increase in mRNA expression and protein concentration in the nr cerebellum of tissue plasminogen activator (tPA), a gene closely linked to the mapped but as-yet-uncloned nr locus. Evidence that excessive tPA triggers nr PN death was obtained with organotypic slice cultures expressing the nr PN phenotype, in which an inhibitor of tPA led to increased nr PN survival. An antagonist of protein kinase C, a downstream component in the tPA pathway, also increased nr PN survival. Additional downstream targets in the tPA pathway (the mitochondrial voltage-dependent anion channel, brain-derived neurotrophic factor, and neurotrophin 3) were also abnormal, in parallel with the alterations in PN mitochondrial morphology, dendritic growth, and synaptogenesis that culminate in nr PN death and motor incoordination. We thus propose a molecular pathway by which the excessive tPA in nr cerebellum mediates PN degeneration.

Animals↗
PubMed2005

Small animal SPECT and its place in the matrix of molecular imaging technologies.

Molecular imaging refers to the use of non-invasive imaging techniques to detect signals that originate from molecules, often in the form of an injected tracer, and observe their interaction with a specific cellular target in vivo. Differences in the underlying physical principles of these measurement techniques determine the sensitivity, specificity and length of possible observation of the signal, characteristics that have to be traded off according to the biological question under study. Here, we describe the specific characteristics of single photon emission computed tomography (SPECT) relative to other molecular imaging technologies. SPECT is based on the tracer principle and external radiation detection. It is capable of measuring the biodistribution of minute (<10(-10) molar) concentrations of radio-labelled biomolecules in vivo with sub-millimetre resolution and quantifying the molecular kinetic processes in which they participate. Like some other imaging techniques, SPECT was originally developed for human use and was subsequently adapted for imaging small laboratory animals at high spatial resolution for basic and translational research. Its unique capabilities include (i) the ability to image endogenous ligands such as peptides and antibodies due to the relative ease of labelling these molecules with technetium or iodine, (ii) the ability to measure relatively slow kinetic processes (compared with positron emission tomography, for example) due to the long half-life of the commonly used isotopes and (iii) the ability to probe two or more molecular pathways simultaneously by detecting isotopes with different emission energies. In this paper, we review the technology developments and design tradeoffs that led to the current state-of-the-art in SPECT small animal scanning and describe the position SPECT occupies within the matrix of molecular imaging technologies.

Animals↗
PubMed2005

Comparative functional genomics for identifying models of human cancer.

Genetically modified mice with overexpressed and/or deleted genes have been used extensively to model human cancer. However, it is uncertain as to what extent the mouse models reproduce the corresponding cancers in humans. We have compared the global gene expression patterns in human and mouse hepatocellular carcinomas (HCCs) in an attempt to identify the mouse models that most extensively reproduce the molecular pathways in the human tumors. The comparative analysis of the gene expression patterns in murine and human HCC indicates that certain genetic mouse models closely reproduce the gene expression patterns of HCC in humans, while others do not. Identification of mouse models that reproduce the molecular features of specific human cancers (or subclasses of specific human cancers) promises to accelerate both the understanding of the molecular pathogenesis of cancer and the discovery of therapeutic targets. We propose that this method, comparative functional genomics, could be effectively applied to the analysis of mouse models for other human cancers.

Animals↗
PubMed2006

Synergistic antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, with gemcitabine and ionizing radiation against pancreatic cancer.

PURPOSE: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination. EXPERIMENTAL DESIGN: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1 cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count. RESULTS: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone. CONCLUSIONS: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.

Animals↗
PubMed2006

Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway.

It is now 100 years since the nosological definition of Alzheimer's disease emerged. In the first 80 years, very little progress was made in understanding the mechanisms that caused the brain to degenerate in a remarkably specific fashion (amyloid accumulation with neurofibrillary changes). Over the past 20 years, there has been an explosion of knowledge which continues today at an exponential rate. The molecular pathways underlying the synaptic dysfunction in Alzheimer's disease have delivered many validated therapeutic and diagnostic targets. A variety of therapeutic strategies aimed at disease modification are now in clinical development.

Alzheimer Disease↗