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At least 433 records · Page 24Linked to original sources
PubMed2004

Gene expression profiles and genetic damage in benzo(a)pyrene diol epoxide-exposed TK6 cells.

Microarray analysis is a powerful tool to identify the biological effects of drugs or chemicals on cellular gene expression. In this study, we compare the relationships between traditional measures of genetic toxicology and mutagen-induced alterations in gene expression profiles. TK6 cells were incubated with 0.01, 0.1, or 1.0 microM +/-anti-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide (BPDE) for 4 h and then cultured for an additional 20 h. Aliquots of the exposed cells were removed at 4 and 24 h in order to quantify DNA adduct levels by 32P post-labeling and measure cell viability by cloning efficiency and flow cytometry. Gene expression profiles were developed by extracting total RNA from the control and exposed cells at 4 and 24 h, labeling with Cy3 or Cy5 and hybridizing to a human 350 gene array. Mutant frequencies in the Thymidine Kinase and Hypoxanthine Phosphoribosyl Transferase genes were also determined. The 10alpha-(deoxyguanosin-N(2)-yl)-7alpha,8beta,9beta-trihydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (dG-N(2)-BPDE) adduct increased as a function of dose and was the only adduct identified. A dose-related decrease in cell viability was evident at 24 h, but not at 4 h. Cell death occurred by apoptosis. At 4 h, analysis of the gene expression profiles revealed that Glutathione Peroxidase and Gadd45 were consistently upregulated (greater than 1.5-fold and significantly (P < 0.001) greater than the control in two experiments) in response to 1.0 microM BPDE exposure. Fifteen genes were consistently down-regulated (less than 0.67-fold and significantly (P < 0.001) lower than the control in two experiments) at 4 h in cultures exposed to 1.0 microM BPDE. Genes with altered expression at 4 h included genes important in the progression of the cell-cycle and those that inhibit apoptosis. At 24 h post-exposure, 16 genes, involved in cell-cycle control, detoxification, and apoptosis were consistently upregulated; 10 genes were repressed in cultures exposed to the high dose of BPDE. Real-time quantitative PCR confirmed the differential expression of selected genes. These data suggest that changes in gene expression will help to identify effects of drugs and chemicals on molecular pathways in cells, and will provide useful information about the molecular responses associated with DNA damage. Of the endpoints evaluated, DNA adduct formation was the most sensitive indicator of DNA damage. DNA adduct formation was clearly evident at low doses, but the number of genes with significantly altered expression (P < 0.001) was minimal. Alterations in gene expression were more robust at doses associated with cellular toxicity and induction of mutations.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2006

Inhibition of cyclic strain-induced endothelin-1 secretion by baicalein in human umbilical vein endothelial cells.

Baicalein is a flavonoid extracted from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in Oriental medicine. Among its biological activities, baicalein has been reported to exhibit antioxidant effects. Endothelin-1 (ET-1) is a potent vasopressor synthesized by endothelial cells both in culture and in vivo. The aims of this study were to test the hypothesis that baicalein may alter strain-induced ET-1 secretion and to identify the putative underlying signaling pathways in endothelial cells. We show that baicalein inhibited strain-induced ET-1 secretion. Baicalein also inhibited strain-increased reactive oxygen species (ROS) formation and the extracellular signal-regulated kinases (ERK) phosphorylation. Using a reporter gene assay, baicalein and the antioxidant Trolox also attenuated the strain-stimulated activator protein-1 (AP-1) reporter activity. We conclude that baicalein inhibits strain-induced ET-1 gene expression, partially by interfering with the ERK pathway via attenuation of ROS formation. These results highlight the molecular pathways that may contribute to the beneficial effects of baicalein in the vascular system such as stroke prevention.

Antioxidants↗
PubMed2007

Carney complex: the first 20 years.

PURPOSE OF REVIEW: The purpose of this review is to comment on the current findings on Carney complex, a dominantly inherited disease and a unique multiple endocrine neoplasia syndrome. RECENT FINDINGS: Sequencing of the PRKAR1A gene in more than 150 kindreds has revealed a number of pathogenic mutations; in more than 90% of the cases, the sequence change was predicted to lead to a premature stop codon and, thus, mutant mRNAs were subject to nonsense-mediated mRNA decay. In Carney complex syndrome cells carrying these mutations, protein kinase A activity is irregularly stimulated by cAMP. Mutations that did not lead to a premature stop codon have also been described; these were also associated with abnormal protein kinase A activity. Animal models of the disease have been recently developed; they reproduced some of the stigmata of Carney complex syndrome but not all. Genetic testing of patients' family members has been introduced in recent years, leading to early detection and a better overall prognosis. SUMMARY: New treatments have yet to be applied; the elucidation of the molecular pathways regulated by PRKAR1A holds the promise of leading to molecularly designed therapies.

Acromegaly↗
PubMed2002

Resveratrol suppresses angiotensin II-induced Akt/protein kinase B and p70 S6 kinase phosphorylation and subsequent hypertrophy in rat aortic smooth muscle cells.

Resveratrol (RV), a polyphenolic substance found in grape skin, is proposed to account in part for the protective effect of red wine in the cardiovascular system. Angiotensin II (Ang II)-induced hypertrophy of vascular smooth muscle cells (VSMCs) is a pivotal step in the development of cardiovascular disease. The aims of this study were to test the hypothesis that RV may alter Ang II-mediated hypertrophic VSMC growth and to identify the putative underlying signaling pathways. We show that RV indeed potently inhibits Ang II-induced [(3)H]leucine incorporation in a concentration-dependent manner (50 microM RV, 71% inhibition). Western blot analysis reveals that phosphorylation of Akt/protein kinase B (PKB) and to a lesser extent the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) 1/2, both essentially involved in Ang II-mediated hypertrophy, is dose dependently reduced by RV. Consistent with these results, we show that RV attenuates phosphorylation of the p70 ribosomal protein S6 kinase (p70(S6K)), a kinase downstream of the ERK 1/2 as well as the Akt pathway, that is implicated in Ang II-induced protein synthesis. Upstream of Akt/PKB RV seems to mediate its antihypertrophic effect by inhibiting phosphorylation of the phosphatidylinositol 3-kinase (PI(3)K) rather than by activating phosphatases. In summary, we demonstrate for the first time that RV inhibits Ang II-induced VSMC hypertrophy, possibly by interfering mainly with the PI(3)K/Akt and p70(S6K) but also with the ERK 1/2 signaling pathway. Thus, this study delivers important new insight in the molecular pathways that may contribute to the proposed beneficial effects of RV in cardiovascular disease.

Angiotensin II↗
PubMed2000

Critical temporal modulation of neuronal programmed cell injury.

1. As a free radical, nitric oxide (NO) may be toxic to neurons through mechanisms that directly involve DNA damage. Lubeluzole, a novel benzothiazole compound, has recently been demonstrated to be neuroprotective through the signal transduction pathways of NO. We therefore examined whether neuroprotection by lubeluzole was dependent upon the molecular pathways of programmed cell death (PCD). 2. In primary hippocampal neurons, evidence of PCD was determined by hematoxylin and eosin (H&E) stain, transmission electron microscopy, and annexin-V binding. NO administration with the NO generators sodium nitroprusside (300 microM) or SIN-1 (300 microM) directly induced PCD. 3. Neurons positive for PCD increased from 22+/-3% (untreated) to 72+/-3% (NO) over a 24-hr period. Coadministration of NO and lubeluzole (750 nM), a neuroprotective concentration, actively decreased PCD expression on H&E stain from 72+/-3% (NO only) to 25+/-3% (NO and lubeluzole). Significant reduction in DNA fragmentation by lubeluzole also was evident on electron microscopy. Application of lubeluzole in concentrations that were not neuroprotective or administration of the biologically inactive R-isomer did not significantly alter NO-induced PCD, suggesting that neuroprotection by lubeluzole was intimately linked to the modulation of PCD. Lubeluzole also was able to prevent the initial stages of cellular membrane inversion labeled with annexin-V binding, an early and sensitive indicator of PCD. Interestingly, the critical period for lubeluzole to reverse PCD induction appeared to be within the first 4 hr following NO exposure. 4. Further investigation into the neuroprotective pathways that alter PCD may provide greater insight into the molecular mechanisms that ultimately determine neuronal injury.

Animals↗
PubMed2005

Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1.

Estrogen signaling occurs through at least two distinct molecular pathways: (i) direct binding of liganded estrogen receptors (ERs) to estrogen-responsive DNA elements (EREs) (the "ER/ERE pathway") and (ii) indirect recruitment of liganded ERs to activating protein-1 (AP-1)-responsive DNA elements via heterodimers of Fos and Jun (the "ER/AP-1 pathway"). We have developed a biochemical assay for examining ligand-regulated transcription by ERs in the ER/AP-1 pathway. This assay recapitulates the altered (i.e., agonistic) pharmacology of selective estrogen receptor modulator drugs in this pathway reported previously by using various cell-based assays. We used our biochemical assay to examine the detailed mechanisms of ER/AP-1-dependent transcription. Our studies indicate that (i) ERalpha/AP-1 complexes play a critical role in promoting the formation of stable RNA polymerase II preinitiation complexes leading to transcription initiation, (ii) chromatin is a key determinant of estrogen and selective estrogen receptor modulator signaling in the ERalpha/AP-1 pathway, (iii) distinct domains of ERalpha are required for recruitment to DNA-bound Fos/Jun heterodimers and transcriptional activation at AP-1 sites, and (iv) different enhancer/activator combinations in the ERalpha and AP-1 pathways use coactivators in distinct ways. These studies have increased our understanding of the molecular mechanisms underlying ligand-dependent signaling in the ER/AP-1 pathway and demonstrate the usefulness of this biochemical approach.

Chromatin↗
PubMed2005

Mixed lineage kinase-c-jun N-terminal kinase signaling pathway: a new therapeutic target in Parkinson's disease.

There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) -c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway.

Animals↗
PubMed2006

Cell cycle molecules define a pathway required for neuron death in development and disease.

We review here evidence defining a molecular pathway that includes cell cycle-related molecules and that appears to play a required role in neuron death during normal development as well as in disease and trauma. The pathway starts with inappropriate activation of cyclin dependent kinase 4 (Cdk4) in neurons which leads to hyper-phosphorylation of the pRb family member p130. This in turn results in dissociation of p130 and its associated chromatin modifiers Suv39H1 and HDAC1 from the transcription factor E2F4. Dissociation of this complex results in de-repression of genes with E2F binding sites including those encoding the transcription factors B- and C-Myb. Once elevated in neurons, B- and C-Myb proteins bind to the promoter for the pro-apoptotic BH3-only protein Bim and promote its induction. Bim then interacts with the core cellular apoptotic machinery, leading to caspase activation and apoptotic death. This pathway is supported by a variety of observations and experimental findings that implicate it as a required element for neuron loss in development and in many nervous system traumas and disorders. The components of this pathway appear to represent potential therapeutic targets for prevention of disease-associated neuron death.

Animals↗
PubMed2004

Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway.

BACKGROUND: Microbial superantigens induce human T-cell resistance to corticosteroids. OBJECTIVE: Understanding the molecular pathways resulting in corticosteroid-resistant T cells is important because this condition can complicate the treatment of inflammation. METHODS: The response of human PBMCs to steroids was assessed by using proliferation assays after stimulation with superantigens or anti-CD3 in the presence of various kinase inhibitors. Glucocorticoid receptor alpha (GCRalpha) localization was defined on the basis of intracellular staining. Protein phosphorylation was measured by means of Western blotting. RESULTS: In the current study we found that PBMCs stimulated with superantigen, but not anti-CD3, induced corticosteroid-resistant T cells. However, the purified T cells stimulated either with staphylococcal enterotoxin B (SEB) or anti-CD3 are susceptible to corticosteroid inhibition. These results imply that signals on antigen-presenting cells might act in concert with the T-cell receptor to cause steroid resistance. Blockade of CD40-CD40 ligand interaction had no effect on superantigen-induced corticosteroid resistance. However, CD28 costimulation with T-cell receptor activation induced corticosteroid resistance of human T cells in a dose-dependent manner. Superantigen stimulation, compared with anti-CD3 stimulation, was found to induce a more rapid and sustained phosphorylation of mitogen-activated extracellular signal-regulated kinase (ERK). Treatment with PD98059 and UO126 (specific mitogen-activated protein kinase kinase [MEK]/ERK inhibitors), but not a p38 inhibitor or a c-Jun N-terminal kinase inhibitor, restored the response to steroids, as indicated by proliferation assays. Furthermore, purified ERK1 and ERK2 were able to phosphorylate recombinant human GCRalpha directly in an in vitro kinase assay. Of note, superantigen-induced corticosteroid resistance was associated with abrogation of GCRalpha nuclear translocation. This effect could be reversed by treatment with MEK/ERK pathway inhibitors. CONCLUSIONS: These data are compatible with the hypothesis that superantigen-induced corticosteroid resistance involves the Raf-MEK-ERK1/ERK2 pathway of T-cell receptor signaling, which leads to GCRalpha phosphorylation and inhibition of dexamethasone-induced GCRalpha nuclear translocation.

Active Transport, Cell Nucleus↗
PubMed2002

A bioinformatics-based strategy identifies c-Myc and Cdc25A as candidates for the Apmt mammary tumor latency modifiers.

The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. On the basis of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c-Myc, both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding polymorphism in both genes, in the promoter region of Cdc25A, and in the 3' UTR of c-Myc. Molecular and in vitro analysis showed that the polymorphisms were functionally significant. In vivo analysis was performed by generating compound PyVT/Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c-Myc and Cdc25A are Apmt1 and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.

3T3 Cells↗
PubMed2006

Peripheral blood gene expression signature mirrors central nervous system disease: the model of multiple sclerosis.

Global gene expression analysis using cDNA microarrays has proven to be a sensitive method to gain insight into molecular pathways mediating multiple sclerosis (MS) activity and to develop and refine the molecular taxonomy of the disease. This method was applied as a tool to investigate molecular heterogeneity of MS related gene transcripts in the aim of distinguishing between transcripts that trigger disease activity and account for direct genotype-phenotype correlation, and those whose expression is altered as a downstream effect of other genes. This review summarizes the current state of gene expression microarray applications for the study of MS, and specifically emphasizes the results of gene expression studies using peripheral blood mononuclear cells (PBMC) that were shown to be useful for better understanding of disease related pathways, monitoring of therapeutic responses to various drugs and prediction of clinical outcome. In the long run it is expected that the information provided by cDNA microarrays experiments will allow the determination of key molecular players involved in MS pathogenesis, and lead to better management of the disease using targeted treatments that will prevent its progression.

Brain↗
PubMed2005

Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development.

The primary event in mammalian sexual development is the differentiation of the bipotential gonads into either testes or ovaries. Our understanding of the molecular pathways specifying gonadal differentiation is still incomplete. To identify the initial molecular changes accompanying gonadal differentiation in mice, we have performed a large-scale transcriptional analysis of XX and XY Sf1-positive gonadal cells during sex determination. In both male and female genital ridges, a robust genetic program is initiated pre-dating the first morphological changes of the differentiating gonads. Between E10.5 and E13.5, 2306 genes were expressed in a sex-specific manner in the somatic compartment of the gonads; 1223 were overexpressed in XX embryos and 1083 in XY embryos. Although sexually dimorphic genes were scattered throughout the mouse genome, we identified chromosomal regions hosting clusters of genes displaying similar expression profiles. The cyclin-dependent kinase inhibitors Cdkn1a and Cdkn1c are overexpressed in XX gonads at E11.5 and E12.5, suggesting that the increased proliferation of XY gonads relative to XX gonads may result from the overexpression of cell cycle inhibitors in the developing ovaries. These studies define the major characteristics of testicular and ovarian transcriptional programs and reveal the richness of signaling processes in differentiation of the bipotential gonads into testes and ovaries.

Animals↗
PubMed2000

A critical analysis of the use of p53 as a marker for management of bladder cancer.

Delineating the important molecular pathways in carcinogenesis has helped develop and advance the field of molecular diagnosis. Bladder cancer has served as an excellent model in translating some of the advances from the laboratory to clinical settings. Many investigators have examined the use of p53 to help manage patients with bladder cancer who are at high risk of tumor progression. This article reviews the clinical studies that have used p53 as a marker in bladder carcinoma and concludes by determining whether routine assessment of the p53 tumor suppressor gene/protein is indicated at this time.

BCG Vaccine↗
PubMed2002

Parkinson's genetics: molecular insights for the new millennium.

In idiopathic Parkinson's disease and familial parkinsonism, the limited number of overlapping clinical and pathological outcomes argue that a common underlying molecular pathway is perturbed. Genetic methods are a powerful approach to identify molecular components of disease. We summarize recent attempts to identify the genetic components of familial parkinsonism, without a priori assumptions about disease causation. Much effort has been expended on mapping in families with early-onset disease, in which parkinsonism appears inherited as a Mendelian trait. More recently, association methods have been employed in late-onset disease using affected sib-pairs and population isolates. These findings have been extrapolated to Parkinson's disease in the community with some success. We review the molecular synthesis now emerging from a genetic perspective.

Animals↗
PubMed1998

Integrin signalling and tyrosine phosphorylation: just the FAKs?

The integrin family of transmembrane receptors have long been recognized for their structural roles in linking extracellular matrix proteins with the cellular actin cytoskeleton to regulate cell shape, cell migration and tissue architecture. Lately, it has become clear that integrin receptors can initiate intracellular signals that synergize with those from growth-factor receptor protein-tyrosine kinases in modulating cell growth. This review describes our current knowledge of integrin-stimulated tyrosine phosphorylation events and downstream signalling pathways, with emphasis on the recent progress made in understanding the molecular pathways linking the integrin receptors with mitogen-activated protein (MAP) kinase cascades.

Animals↗
PubMed2006

Molecular changes in brain tumors: prognostic and therapeutic impact.

PURPOSE OF REVIEW: This review focuses on recent advances in the molecular biology of the main primary brain tumors (gliomas, medulloblastomas, and ependymomas), with particular emphasis on prognostic markers and potential therapeutic targets. RECENT FINDINGS: Current biologic markers are useful for predicting prognosis (e.g. 1p/19q codeletion in grade 2 and 3 gliomas, nuclear beta-catenin expression in medulloblastoma) or response to the treatment (e.g. the methyl guanyl methyl transferase promoter methylation status). Recent gene profiling studies have identified specific molecular signatures that permit a molecular classification and that also provide new, potentially useful prognostic markers. The studies have also shown a striking parallel between central nervous system ontogenesis and the oncogenesis of brain tumors. By elucidating the underlying activated molecular pathways, these approaches provide the basis for a biologic therapy to target the critically activated pathways. SUMMARY: Important advances have been made in the biologic understanding, molecular subclassification, and identification of prognostic markers in brain tumors, thereby improving the current classifications. Such data provide a rational basis for current and future targeted biologically based strategies.

Antineoplastic Agents↗
PubMed1991

Diversity in receptor signalling: cellular individuality and the search for selective drugs.

Recent developments in the molecular pharmacology of receptor signalling are reviewed. Receptors and other signalling molecules belong to superfamilies characterized by variations on given themes. A remarkable degree of diversity is generated by unique combinations of molecular entities, and there are also interactions between parallel signal transduction pathways. Molecular biology techniques have revealed new targets for drug development, as well as new methods of drug testing. However, it is not yet clear whether molecular and biochemical specificity always correspond to clinical selectivity.

Animals↗
PubMed1992

12-O-tetradecanoylphorbol-13-acetate induces transient cell cycle arrest in G1 and G2 in metastatic melanoma cells: inhibition of phosphorylation of p34cdc2.

The growth of Demel human metastatic melanoma cells was inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA) and other nonphorbol tumor promoters including palytoxin and okadaic acid. Using flow cytometry, we have demonstrated that the cells arrested growth in G1 and G2 phases of the cell cycle. Detailed analysis of the kinetics of the growth arrest in unsynchronized cells showed that (a) the growth arrest was transient and peaked 16-20 h following addition of TPA; (b) effects of TPA on cell growth began within 1-2 h after the addition; and (c) cells completed S phase and arrested in G2. In addition, TPA induced a pronounced morphological change, which peaked by 1 h and gradually subsided over 24 h. In populations of cells synchronized in G1 using lovastatin, (a) addition of TPA blocked the onset of DNA synthesis up to the end of G1; (b) the lag between addition of the drug and onset of DNA synthesis was less than 30 min; and (c) addition of TPA at the end of G1 prevented the increased phosphorylation of p34cdc2, as determined by immunoprecipitation. The experiments reported here show that TPA transiently blocked the proliferation of Demel melanoma cells at the G1-S border and in G2, thus preventing cells from progressing through the cell cycle. These experiments suggest that pathways involving protein kinase C interact with and rapidly alter the molecular pathways involving p34cdc2 which regulate the onset of DNA synthesis and the G2-M transition.

Breast Neoplasms↗