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At least 775 records · Page 43Linked to original sources
PubMed2004

Prenatal origin of chromosomal translocations in acute childhood leukemia: implications and future directions.

We, and others, have demonstrated an in utero origin for translocations associated with childhood leukemia, with latency periods in some cases exceeding 10 years. The mechanism of generation of most of the translocations is thought to be aberrant repair following abortive apoptosis, rather than V(D)J recombination or exposure to topoisomerase II inhibitors. Folate supplementation may prevent some of the chromosome breakage leading to translocation formation. Translocations t(8;21) and t(12;21) have been shown to occur in the normal population (before birth) at a frequency that is 100-fold greater than the risk of developing the corresponding leukemia. In most instances, additional genetic changes are required for progression to leukemia. Tyrosine kinase receptor (RTK) mutations, which give cells a survival/proliferative advantage, are proposed to act cooperatively with fusion genes, leading to transformation. However, translocations and cooperating RTK mutations have not been identified for all leukemia subtypes, particularly in acute myeloid leukemia. The core binding transcriptional pathway is frequently targeted by translocation in utero. We propose that this pathway is highly sensitive during fetal hematopoiesis and may be targeted by mechanisms other than translocation. For each leukemia subtype it is important to characterize the corresponding leukemic stem cell, which is thought to be the initial target for translocation. This would help to elucidate the molecular pathways involved in the progression from preleukemic clone harboring a translocation to fully disseminated leukemia.

Acute Disease↗
PubMed2001

Transcriptome analysis and crop improvement (a review).

The identification and characterization of differential gene expression from tissues subjected to stress has gained much attention in plant research. The recognition of elements involved in the response to a particular stress enhances the possibility of promoting crop improvement through direct genetic modification. However, the performance of some of the 'first generation' of transgenic plants with the incorporation of a single gene has not always been as expected. These results have stimulated the development of new transgenic constructions introducing more than one gene and capable of modifying complex pathways. Several techniques are available to conduct the analysis of gene regulation, with such information providing the basis for novel constructs specifically designed to modify metabolism. This review deals with techniques that allow the identification and characterization of differentially-expressed genes and the use of molecular pathway information to produce transgenic plants.

DNA Fingerprinting↗
PubMed2003

Cyclic expression of esr9 gene in Xenopus presomitic mesoderm.

During somitogenesis, the cycling expression of members of the Notch signalling cascade is involved in a segmentation clock that regulates the periodic budding of somites in chicken, mouse, and zebrafish. In frog, genes with cycling expression in the presomitic mesoderm have not been reported. Here, we describe the expression of Xenopus esr9 and esr10, two new members of the Hairy/Enhancer of split related family of bHLH proteins. We show that they are expressed in a highly dynamic fashion, with their mRNA levels oscillating periodically in the presomitic mesoderm during somitogenesis. This dynamic expression is independent of de novo protein synthesis. Thus, expression of esr9 and esr10 is an indicator of the segmentation clock in the amphibian embryo. This confirms the evolutionary conservation of a molecular pathway involved in vertebrate segmentation clock.

Amino Acid Sequence↗
PubMed2000

Intra- and intermolecular events direct the propeptide-mediated maturation of the Candida albicans secreted aspartic proteinase Sap1p.

Pathogenic yeasts of the genus Candida secrete aspartic proteinases (Sap) which are synthesized as preproenzymes. Expression of the C. albicans SAP1 gene lacking the propeptide-coding region in the methylotrophic yeast Pichia pastoris does not lead to the secretion of the enzyme into the culture supernatant, but results in an accumulation of recombinant protein in the cell. Co-expression in this system of the unattached propeptide from Sap1p, as well as from other Saps, restored Sap1p secretion. A deletion analysis revealed that only a 12 aa sequence in the propeptide, corresponding to a highly conserved region in all Sap propeptides, was necessary and sufficient to produce a large amount of Sap1p in culture supernatant. No Sap1p was secreted when Sap1p was produced with a propeptide carrying an F to D mutation in the identified 12 aa sequence. However, the simultaneous production of equivalent amounts of Sap1p and His-tagged Sap1p (H(6)-Sap1p) with a mutated and a non-mutated propeptide, respectively, led to the secretion of both proteins in a ratio of approximately 1:2. The restoration of Sap1p secretion occurred at the expense of secretion of H(6)-Sap1p since the total activity was comparable to that of strains producing only H(6)-Sap1p with a non-mutated propeptide. In contrast, the proteolytic activity of strains secreting Sap1p and H(6)-Sap1p both with a functional propeptide was twice that of strains producing either Sap1p or H(6)-Sap1p alone, and the two enzymes were found in an equivalent amount in the culture supernatant. Altogether, these results show that the propeptide can only function once and that the maturation of recombinant C. albicans secreted aspartic proteinase Sap1p is directed through a combination of intra- and inter-molecular pathways.

Amino Acid Sequence↗
PubMed2007

NF-kappaB pathway is involved in griseofulvin-induced G2/M arrest and apoptosis in HL-60 cells.

Griseofulvin (GF), an oral antifungal agent, has been shown to exert antitumorigenesis effect through G2/M cell cycle arrest in colon cancer cells. But the underlying mechanisms remained obscure. The purpose of this study is to test the cytotoxic effect of GF on HL-60 and HT-29 cells and elucidate its underlying molecular pathways. Dose-dependent and time-course studies by flow cytometry demonstrated that 30 to 60 microM GF significantly induced G2/M arrest and to a less extend, apoptosis, in HL-60 cells. In contrast, only G2/M arrest was observed in HT-29 cells under similar condition. Pretreatment of 30 microM TPCK, a serine protease inhibitor, completely reversed GF-induced G2/M cell cycle arrest and apoptosis in HL-60 cells but not in HT-29 cells. The GF-induced G2/M arrest in HL-60 cells is reversible. Using EMSA and super-shift analysis, we demonstrated that GF stimulated NF-kappaB binding activity in HL-60 cells, which was completely inhibited by pretreatment of TPCK. Treatment of HL-60 with 30 microM GF activated JNK but not ERK or p38 MAPK and subsequently resulted in phosphorylation of Bcl-2. Pretreatment of TPCK to HL-60 cells blocked the GF-induced Bcl-2 phosphorylation but not JNK activation. Time course study demonstrated that activation of cdc-2 kinase activity by GF correlated with Bcl-2 phosphorylation. Taken together, our results suggest that activation of NF-kappaB pathway with cdc-2 activation and phosphorylation of Bcl-2 might be involved in G2/M cell cycle arrest in HL-60 cells.

Antifungal Agents↗
PubMed2002

Aging in fungi: role of mitochondria in Podospora anserina.

In experimental gerontology, there is a long tradition in the use of both unicellular and filamentous species of fungi. In the last three decades, biochemical, genetic and molecular approaches have proved very fruitful in elucidating different aspects of ageing. It was shown that various genes and molecular pathways are involved in life span control. The oxygenic energy metabolism plays a central role. During mitochondrial energy transduction, reactive oxygen species (ROS) are generated as by-products. These molecules are able to damage all cellular compounds leading to cellular dysfunctions. Within certain limits, however, cells are able to cope with ROS-related problems. First, ROS scavengers can be induced which are effective in lowering the molecular burden of ROS on cellular functions. Second, if damage occurs, specific repair mechanisms and the general turnover of affected molecules can maintain cellular functions. Finally, if damage of essential components is too severe, cells may induce specific pathways to compensate for the corresponding impairments. A coordinated interaction between different cellular compartments is involved in these processes. In this review I shall concentrate on the ageing in the filamentous ascomycete Podospora anserina. It is clear that both environmental as well as genetic traits are involved in the control of life span and that mitochondrial-nuclear interactions play a paramount role.

Aging↗
PubMed2005

Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia.

There is increasing evidence that a variety of neoplasms including breast cancer may result from transformation of normal stem and progenitor cells. In the past, isolation and characterization of mammary stem cells has been limited by the lack of suitable culture systems able to maintain these cells in an undifferentiated state in vitro. We have recently described a culture system in which human mammary stem and progenitor cells are able to survive in suspension and produce spherical colonies composed of both stem and progenitor cells. Recent observation that adult stem cells from other tissues may also retain the capacity for growth under anchorage independent conditions suggests a common underlying mechanism. We propose that this mechanism involves the interaction between the canonical Wnt signal pathway and E-cadherin. The Wnt pathway has been implicated in normal stem cell self-renewal in vivo. Furthermore, there is evidence that deregulation of this pathway in the mammary gland and other organs may play a key role in carcinogenesis. Thus, the development of in vitro suspension culture systems not only provides an important new tool for the study of mammary cell biology, but also may have important implications for understanding key molecular pathways in both normal and neoplastic stem cells.

Animals↗
PubMed2005

Parkinson's disease: from causes to mechanisms.

Parkinson's disease (PD) is a common age-related, progressive neurodegenerative disease of unknown etiology. Environmental factors have long been suspected to participate in the pathogenesis of PD due to the existence of neurotoxins that preferentially damage the dopaminergic nigrostriatal pathway. In the past few years, novel insights into the degenerative process have been provided by the discovery of genes responsible for rare monogenic parkinsonian syndromes. Compelling evidence is accumulating, suggesting that the products of several of these genes can interact with environmental toxins and intervene in molecular pathways controlling the functional integrity of mitochondria.

Corpus Striatum↗
PubMed2006

Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation.

A central challenge in embryonic development is to understand how growth and pattern are coordinated to direct emerging new territories during morphogenesis. Here, we report on a signaling cascade that links cell proliferation and fate, promoting formation of a distinct progenitor domain within the developing chick hypothalamus. We show that the downregulation of Shh in floor plate-like cells in the forebrain governs their progression to a distinctive, proliferating hypothalamic progenitor domain. Shh downregulation occurs via a local BMP-Tbx2 pathway, Tbx2 acting to repress Shh expression. We show in vivo and in vitro that forced maintenance of Shh in hypothalamic progenitors prevents their normal morphogenesis, leading to maintenance of the Shh receptor, ptc, and preventing progression to an Emx2(+)-proliferative progenitor state. Our data identify a molecular pathway for the downregulation of Shh via a BMP-Tbx2 pathway and provide a mechanism for expansion of a discrete progenitor domain within the developing forebrain.

Animals↗
PubMed2004

DNA microarrays in the diagnosis and management of acute lymphoblastic leukemia.

The significant progress in the treatment of acute lymphoblastic leukemia (ALL) experienced over the last 3 decades has been driven mainly by the empirical combination of antileukemic drugs in highly intensive therapies. Further progress in the management of ALL is currently limited, however, by our incomplete understanding of the molecular pathways involved in leukemia pathogenesis and by the lack of useful prognostic markers for most patients. The recent development of microarray technology, which allows the simultaneous analysis of gene expression levels for thousands of transcripts, has accelerated significantly the rate of progress in our understanding of the molecular basis of ALL. During the last few years, analysis of ALL samples with DNA arrays has facilitated the recognition of molecularly distinct leukemia groups, advanced our knowledge of the mechanisms of sensitivity and resistance to chemotherapy, generated novel prognostic prediction tools, and identified new targets for the development of molecularly tailored antileukemic agents. Thus, the introduction of microarray gene expression profiling has opened the opportunity for accelerated progress in the diagnosis and therapy of ALL, which will ultimately result in the development of novel highly effective and less toxic treatments for this disease.

Biomarkers, Tumor↗
PubMed2001

Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling.

Androgen deprivation therapy for advanced prostate cancer is often effective, but not curative. Molecular pathways mediating the therapeutic response and those contributing to the subsequent hormone-refractory cell growth remain poorly understood. Here, cDNA microarray analysis of human CWR22 prostate cancer xenografts during the course of androgen deprivation therapy revealed distinct global gene expression profiles in primary, regressing and recurrent tumors. Elucidation of the genes involved in the transition between these states implicated specific molecular mechanisms in therapy failure and tumor progression. First, we identified a set of androgen-responsive genes whose expression decreased during the therapy response, but was then systematically restored in the recurrent tumors. In addition, altered expression of genes that encode known targets of rapamycin or that converge on the PI3K/AKT/FRAP pathway was observed in the recurrent tumors. Further suggestion for the involvement of these genes in hormone-refractory prostate cancer came from the observation that cells established from the recurrent xenografts were strongly inhibited in vitro by rapamycin. The results of this functional genomic analysis suggest that the combined effect of re-expression of androgen-responsive genes as well as the activation of rapamycin-sensitive signaling may drive prostate cancer progression, and contribute to the failure of androgen-deprivation therapy.

Algorithms↗
PubMed2006

An integrative genomic approach to uncover molecular mechanisms of prokaryotic traits.

With mounting availability of genomic and phenotypic databases, data integration and mining become increasingly challenging. While efforts have been put forward to analyze prokaryotic phenotypes, current computational technologies either lack high throughput capacity for genomic scale analysis, or are limited in their capability to integrate and mine data across different scales of biology. Consequently, simultaneous analysis of associations among genomes, phenotypes, and gene functions is prohibited. Here, we developed a high throughput computational approach, and demonstrated for the first time the feasibility of integrating large quantities of prokaryotic phenotypes along with genomic datasets for mining across multiple scales of biology (protein domains, pathways, molecular functions, and cellular processes). Applying this method over 59 fully sequenced prokaryotic species, we identified genetic basis and molecular mechanisms underlying the phenotypes in bacteria. We identified 3,711 significant correlations between 1,499 distinct Pfam and 63 phenotypes, with 2,650 correlations and 1,061 anti-correlations. Manual evaluation of a random sample of these significant correlations showed a minimal precision of 30% (95% confidence interval: 20%-42%; n = 50). We stratified the most significant 478 predictions and subjected 100 to manual evaluation, of which 60 were corroborated in the literature. We furthermore unveiled 10 significant correlations between phenotypes and KEGG pathways, eight of which were corroborated in the evaluation, and 309 significant correlations between phenotypes and 166 GO concepts evaluated using a random sample (minimal precision = 72%; 95% confidence interval: 60%-80%; n = 50). Additionally, we conducted a novel large-scale phenomic visualization analysis to provide insight into the modular nature of common molecular mechanisms spanning multiple biological scales and reused by related phenotypes (metaphenotypes). We propose that this method elucidates which classes of molecular mechanisms are associated with phenotypes or metaphenotypes and holds promise in facilitating a computable systems biology approach to genomic and biomedical research.

Algorithms↗
PubMed1992

Allelic loss on chromosome 11p is a less frequent event in bilateral than in unilateral Wilms' tumours.

Analyses to detect loss of heterozygosity (LOH) were performed at 11 polymorphic loci on chromosome 11 and, using a polymorphic CA repeat sequence in the WT1 gene, on a series of 39 tumours from 28 unilateral and 10 tumours from 6 bilateral Wilms' tumour (WT) patients. LOH was seen in 13 out of 35 patients including 12 out of 29 unilateral tumours, but only one of 10 bilateral tumours. This suggests that bilateral WT represents a subgroup of WT in which tumour initiating events less frequently involve LOH on chromosome 11 and that either epigenetic events, point mutations or another non-chromosome 11p locus are important in bilateral tumours. The observation of LOH in one WT but not another WT in a bilateral WT patient provides evidence that these tumours arising in the same patient are not monoclonal proliferations and most likely arise via different molecular pathways.

Alleles↗
PubMed2005

Dose-response effects of ectopic agouti protein on iron overload and age-associated aspects of the Avy/a obese mouse phenome.

Isogenic and congenic offspring from matings of inbred black a/a dams by sibling (or non-sibling from another inbred strain) yellow agouti Avy/a sires provide an animal model of obese yellow agouti Avy/a and isogenic lean pseudoagouti Avy/a mice exhibiting two different in vivo concentrations (high, very low) of ectopic agouti protein (ASP) with congenic lean black a/a mice as null controls. This makes it possible to differentiate between the high and very low dose levels of ectopic ASP with respect to interactions with diverse physiological and molecular pathways. Assay of differential responses to 12 or 24 months of carbonyl iron overload assessed the possible suitability of this animal model for the study of hemochromatosis. Agouti A/a B6C3F1 mice were used as non-congenic null controls. The age-related waxing and waning of body weight, food consumption, and caloric efficiency, as well as associated changes in pancreatic islets and islet cells, and formation of liver tumors were assayed. While the hypothesis that these mice might serve as a tool for investigating hemochromatosis was not confirmed, the data did provide evidence that even the very low levels of ASP in pseudoagouti Avy/a mice affect the network of molecular/metabolic/physiological response pathways that comprises the yellow agouti obese phenome. We suggest that the combination of yellow agouti Avy/a, pseudoagouti Avy/a, and black a/a congenic mice provides a practical tool for applying a dose-response systems biology approach to understanding the dysregulatory influence of ectopic ASP on the molecular-physiological matrix of the organism.

Aging↗
PubMed1999

Issues in risk assessment from solar particle events.

Uncertainties in risk assessment from solar particle events (SPE) include the role of high linear energy transfer (LET) secondary ions, the assessment of dose-rate effects as they relate to acute injury, the risk of cancer mortality and the modification of health effects due to the stress of spaceflight. We discuss several issues where new knowledge is required for improving estimates of radiation risk from SPE's. Secondary particles such as neutrons and low energy and charge ions (LZE) may dominate radiation risk behind a storm shelter and their biological effects are poorly understood, especially at low dose-rate. Dose-rate modulation of radiation response is also related to genetic pre-disposition an important determinant of radiation sensitivity. Molecular pathways that control cell death and tissue response have been elucidated in recent years and should provide new understanding of dose-rate effects for risk assessment. We consider some of these factors and discuss calculations using radiation transport codes, track structure models of energy deposition, and a molecular kinetics approach to model radiation response.

Apoptosis↗
PubMed2000

Mercury-induced apoptosis in human lymphoid cells: evidence that the apoptotic pathway is mercurial species dependent.

There is growing evidence that heavy metals, in general, and mercurial compounds, in particular, are toxic to the human immune system. In this regard, we have previously shown that both inorganic and organic mercurials are potent human T-cell apoptogens; moreover, mitochondria appear to be a target organelle for the induction of cell death. To ascertain whether both mercury species utilize the same molecular pathway to trigger the apoptotic cascade, cells were treated with MeHgCl or HgCl2 and mitochondrial activity was examined. We show that both mercury species affect mitochondrial activity by inducing the development of a membrane permeability transition. This state is characterized by a decline in both the transmembrane potential and the intracellular pH, as well as the generation of reactive oxygen species. We also determined that mercury exposure results in a decline in the T-cell GSH content. Since mitochondrial dysfunction and the development of a permeability transition may result in the release of cytochrome c, a factor that promotes apoptosis, we assessed the abilities of both species of mercury to induce the translocation of cytochrome c from mitochondria to the cytosol. We noted that MeHgCl caused a significant increase in cytosolic cytochrome c. Surprisingly, however, HgCl2 did not alter the level of cytosolic cytochrome c. We next determined whether the mercurials could alter the level of the anti-apoptotic protein Bcl-2. Our results demonstrate that HgCl2 induces a significant elevation in the Bcl-2 content of T-cells; in contrast, T-cells treated with MeHgCl did not exhibit altered levels of this anti-apoptotic protein. Regardless of whether cytochrome c is released from the mitochondria, both mercurial species were capable of activating the caspase cascade, as evident by cleavage of poly (ADP-ribose) polymerase. Thus, our study shows that, whereas each of the mercury species shares common features in the apoptotic process, profound differences exist in a number of key steps in the pathway. The significance of these differences is discussed.

Adult↗
PubMed2001

Genetic pathways and histogenetic models of AIDS-related lymphomas.

Acquired immunodeficiency syndrome (AIDS)-related lymphomas consistently display a B-cell phenotype and are histogenetically related to germinal centre or post-germinal centre B cells in the overwhelming majority of cases. The pathogenesis of AIDS-related lymphoma is a multistep process involving factors provided by the host as well as alterations intrinsic to the tumour clone. The molecular pathways of viral infection and lesions of cancer-related genes associated with AIDS-related lymphomas vary substantially in different clinicopathological categories of the disease and highlight the marked degree of biological heterogeneity of these lymphomas.

Burkitt Lymphoma↗
PubMed2006

Effect of TNF-alpha on the melatonin synthetic pathway in the rat pineal gland: basis for a 'feedback' of the immune response on circadian timing.

A retino-hypothalamic-sympathetic pathway drives the nocturnal surge of pineal melatonin production that determines the synchronization of pineal function with the environmental light/dark cycle. In many studies, melatonin has been implicated in the modulation of the inflammatory response. However, scant information on the feedback action of molecules present in the blood on the pineal gland during the time course of an inflammatory response is available. Here we analyzed the effect of tumor necrosis factor-alpha (TNF-alpha) and corticosterone on the transcription of the Aa-nat, hiomt and 14-3-3 protein genes in denervated pineal glands of rats stimulated for 5 hr with norepinephrine, using real-time reverse transcription-polymerase chain reaction. The transcription of Aa-nat, a gene encoding the key enzyme in melatonin biosynthesis, together with the synthesis of the melatonin precursor N-acetylserotonin, was inhibited by TNF-alpha. This inhibition was transient, and a preincubation of TNF-alpha for more than 24 hr had no detectable effect. In fact, a protein(s) transcribed, later on, as shown by cycloheximide, was responsible for the reversal of the inhibition of Aa-nat transcription. In addition, corticosterone induced a potentiation of norepinephrine-induced Aa-nat transcription even after 48 hr of incubation. These data support the hypothesis that the nocturnal surge in melatonin is impaired at the beginning of an inflammatory response and restored either during the shutdown of an acute response or in a chronic inflammatory pathology. Here, we introduce a new molecular pathway involved in the feedback of an inflammatory response on pineal activity, and provide a molecular basis for understanding the expression of circadian timing in injured organisms.

Animals↗