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Results for “Candidate pathways”

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PubMed2000

Cloning of DPK, a novel dendritic cell-derived protein kinase activating the ERK1/ERK2 and JNK/SAPK pathways.

Mitogen-activated protein kinase (MAPK) cascades are the major signaling systems transducing extracellular signals into intracellular responses, which mainly include the extracellular signal-regulated kinase (ERK) pathway, the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway, and the p38 pathway. From dendritic cell cDNA library, we isolated a full-length cDNA encoding a potentially novel 898-residue kinase, which was designated DPK. The protein contained a potential kinase domain at the N-terminal exhibiting homology with MEKK1-, MEKK2-, MEKK3-, MEKK4-, MEKK5-, Tpl-2-, and p21-activated kinases (PAKs), but no GTPase-binding domain which is characteristic of PAKs. Northern blotting analysis showed that DPK was ubiquitously expressed in normal tissues, with abundant expression in kidney, skeletal muscle, heart, and liver. When overexpressed in transfected NIH3T3 cells, it could activate both the ERK1/ERK2 pathway and the SAPK pathway in a dose-dependent manner, but not affect the p38 pathway. These findings suggested that DPK might be a novel candidate MAPKKK.

Amino Acid Sequence↗

PubMed2002

Modulation of BMP activity in dorsal-ventral pattern formation by the chordin and ogon antagonists.

We analyzed the interactions between mutations in antagonistic BMP pathway signaling components to examine the roles that the antagonists play in regulating BMP signaling activity. The dorsalized mutants swirl/bmp2b, snailhouse/bmp7, lost-a-fin/alk8, and mini fin/tolloid were each analyzed in double mutant combinations with the ventralized mutants chordino/chordin and ogon, whose molecular nature is not known. Similar to the BMP antagonist chordino, we found that the BMP ligand mutants swirl/bmp2b and snailhouse/bmp7 are also epistatic to the putative BMP pathway antagonist, ogon, excluding a class of intracellular antagonists as candidates for ogon. In ogon;mini fin double mutants, we observed a mutual suppression of the ogon and mini fin mutant phenotypes, frequently to a wild type phenotype. Thus, the Tolloid/Mini fin metalloprotease that normally cleaves and inhibits Chordin activity is dispensable, when Ogon antagonism is reduced. These results suggest that Ogon encodes a Tolloid and Chordin-independent antagonistic function. By analyzing genes whose expression is very sensitive to BMP signaling levels, we found that the absence of Ogon or Chordin antagonism did not increase the BMP activity remaining in swirl/bmp2b or hypomorphic snailhouse/bmp7 mutants. These results, together with other studies, suggest that additional molecules or mechanisms are essential in generating the presumptive gastrula BMP activity gradient that patterns the dorsal-ventral axis. Lastly we observed a striking increased penetrance of the swirl/bmp2b dominant dorsalized phenotype, when Chordin function is also absent. Loss of the BMP antagonist Chordin is expected to increase BMP signaling levels in a swirl heterozygote, but instead we observed an apparent decrease in BMP signaling levels and a loss of ventral tail tissue. As has been proposed for the fly orthologue of chordin, short gastrulation, our paradoxical results can be explained by a model whereby Chordin both antagonizes and promotes BMP activity.

Animals↗

PubMed2004

Apoptosis regulation in the mammary gland.

Epithelial apoptosis has a key role in the development and function of the mammary gland. It is involved with the formation of ducts during puberty and is required to remove excess epithelial cells after lactation so that the gland can be prepared for future pregnancies. Deregulated apoptosis contributes to malignant progression in the genesis of breast cancer. Since epithelial cell apoptosis in the lactating mammary gland can be synchronised by forced weaning, it has been possible to undertake biochemical analysis of the pathways involved. Together with the targeted overexpression or deletion of candidate genes, these approaches have provided a unique insight into the complex mechanisms of apoptosis regulation in vivo. This review explores what is currently known about the triggers for apoptosis in the normal mammary gland, and how they link with the intrinsic apoptotic machinery.

Animals↗

PubMed2004

Pharmacogenetics of antipsychotic-induced weight gain.

RATIONALE: Antipsychotic medications have been associated with considerable weight gain. The degree of inter-individual variability and known genetic contributions to obesity suggest a combination of genetic and environmental factors. In the absence of established mechanisms and valid predictors for this relevant adverse effect, pharmacogenetic studies may provide the basis for the development of individualized treatment and preventive interventions. OBJECTIVE: The aim of the present review is to analyze the theoretical and empirical knowledge base for the selection of the most promising target genes that may contribute to antipsychotic-induced weight gain. METHODS: Examination of the preclinical and clinical literature that can inform the rational choice of target genes that may play a role in the development of adverse changes in body composition associated with antipsychotic treatment. RESULTS: Theoretically, candidate gene selection can be guided by knowledge about molecular pathways associated with obesity, receptors modulated by antipsychotic drugs, and enzymes implicated in their metabolism and bioavailability. While most available data relate to the general mechanisms of obesity and few studies have directly examined the genetic contributions to antipsychotic-induced weight gain, several genes warrant further investigation. These include the 5-HT(2C), pro-opiomelanocortin, leptin, ghrelin, tumor necrosis factor alpha, adiponectin, dopamine D(2) receptor, histamine-H(1) receptor, and alpha(1), beta(2) and beta(3) adrenergic receptor genes. CONCLUSIONS: Pharmacogenetic studies can provide powerful tools for the pre-treatment identification of individuals at high risk for antipsychotic-induced weight gain, to uncover biological mechanisms that may even generalize to non-drug-induced weight gain, and to isolate novel targets for treatments of weight gain and obesity. To enhance power, future studies should pay close attention to population selection and avoidance/control of confounds, particularly past treatment exposure.

Adiponectin↗

PubMed1998

Elite endurance athletes and the ACE I allele--the role of genes in athletic performance.

Genetic markers that might contribute to the making of an elite athlete have not been identified. Potential candidate genes might be found in the renin-angiotensin pathway, which plays a key role in the regulation of both cardiac and vascular physiology. In this study, DNA polymorphisms derived from the angiotensin converting enzyme (ACE), the angiotensin type 1 receptor (AT1) and the angiotensin type 2 receptor (AT2) were studied in 64 Australian national rowers. Compared with a normal population, the rowers had an excess of the ACE I allele (P<0.02) and the ACE II genotype (P=0.03). The ACE I allele is a genetic marker that might be associated with athletic excellence. It is proposed that the underlying mechanism relates to a healthier cardiovascular system.

Adult↗

PubMed2004

Treatment of T-cell non-Hodgkin's lymphoma.

T-cell non-Hodgkin's lymphoma (NHL) represents approximately 10% to 15% of all lymphomas in Western countries. Patients with T-cell NHL are often treated similarly to patients with intermediate grade B-cell NHL, although many reports have demonstrated lower overall survival rates in patients with T-cell NHL compared to patients with B-cell NHL. Updated classifications have recognized specific clinical and pathologic T-cell entities, such as peripheral T-cell lymphoma, not otherwise characterized, angioimmunoblastic lymphoma, systemic anaplastic T-cell lymphoma, adult T-cell leukemia/lymphoma, subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, and enteropathy-type intestinal T-cell lymphoma. Furthermore, these distinct T-cell NHL subtypes often warrant individualized diagnostic and therapeutic strategies, such as the associated cytophagic histiocytic panniculitis and hemophagocytic syndrome with subcutaneous panniculitis-like T-cell lymphoma, the chromosomal translocation t(2;5), leading to the nucleophosmin anaplastic lymphoma kinase fusion protein, viral pathogenesis of Epstein-Barr virus, human T-cell lymphotropic virus type-1 associated with extranodal NK/T-cell lymphoma nasal type and adult T-cell leukemia/lymphoma, respectively, and the role of radiation therapy in extranodal NK/T-cell lymphoma nasal type. Other active therapeutic agents in T-cell NHL include purine and pyrimidine antimetabolite agents (eg, nucleoside analogues and gemcitabine, respectively), denileukin diftitox, and antinucleoside or retinoic acid with interferon-alpha combination treatment. The exact role of transplantation in patients with T-cell NHL is unknown, but several case series have documented the feasibility of autologous and allogeneic transplant with reported long-term survival rates similar to transplanted B-cell NHL. Identification of relevant proto-oncogenes and tumor suppressor genes involved in the pathogenesis of T-cell NHL, such as the nucleophosmin anaplastic lymphoma kinase fusion protein, p53 and retinoblastoma gene, cyclin-dependent kinase inhibitors, histone deacetylation inhibitors, and infectious etiologies (eg, Epstein-Barr virus and Helicobacter pylori), in addition to their interplay with the various regulatory pathways of cell-cycle progression and apoptosis, represent potential candidates for molecular-based therapy. Prospective multi-institution clinical trials are critically important to determine the most effective treatment regimens that will continue to improve cure rates in these aggressive, yet treatable and often curable, diseases.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Disease mechanisms in psoriasis and psoriatic arthritis.

Any hypothesis that tries to explain disease mechanisms in psoriasis and psoriatic arthritis (PsA) must take into account the containment of the inflammatory process to three specific sites: the skin, synovium, and enthesis. This article reviews the recent literature that advances our understanding of disease mechanisms at these specific sites. Additional progress will be achieved by research that focuses on common pathogenic pathways at these sites, in particular when searching for foreign candidates or auto-antigens triggering the T-cell-mediated immune response.

Arthritis, Psoriatic↗

PubMed2025

TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation.

Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identify regulators in glucose-starvation-induced cell death and find a group of genes in lysosomal pathway is enriched following glucose starvation. We focus on one candidate gene, Transcriptional Factor 25 (TCF25). We find TCF25 enhances lysosomal acidification by targeting V-ATPase, promoting autophagy and ATP generation under glucose starvation. However, prolonged glucose starvation constitutively activates ferritinophagy via TCF25, increasing lysosomal membrane permeability (LMP) and leading to lysosome-dependent cell death (LDCD). Knocking out TCF25 or V-ATPase components prevents cell death. Furthermore, TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury. Our findings identify TCF25 as a crucial nutrient sensor that regulates lysosomal activity, offering potential therapeutic targets for metabolic and ischemic disorders.

Lysosomes↗

PubMed1998

Rapid and transient induction of CYP1A1 gene expression in human cells by the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole.

Studies to assess the induction of CYP1A1 gene expression by tryptophan derived oxidation products which are suggested as endogenous ligands for the Ah receptor are described. For the two high affinity Ah receptor ligands produced from tryptophan, the chemical structure was recently identified as 6-formylindolo[3,2-b]carbazole (FICZ) and 6,12-diformylindolo[3,2-b]carbazole (dFICZ), respectively. Therefore these two compounds show a close similarity to the indolecarbinol-derived condensation product indolo[3,2-b]carbazole (ICZ). Incubation of cells from a human keratinocyte (HaCaT) cell line together with ICZ, FICZ, dFICZ and some structurally related indole compounds was performed. The compound with the highest affinity to the Ah receptor, FICZ, was found to be the most efficient inducer of CYP1A1 gene expression in short time incubation (0.5 h) experiments. With longer incubation times (24 h) ICZ was the most efficient inducer. The two most active compounds, FICZ and ICZ, caused increased mRNA levels already at a concentration of 100 pM. FICZ was also shown to increase CYP1A1 mRNA levels in fresh human peripheral blood cells at the same low concentration. FICZ and ICZ were furthermore compared with regard to their capacity to inhibit cDNA-expressed human CYP1A1 enzyme and FICZ was found to be the most potent inhibitor. The inhibition was, however, transient in character indicating that FICZ is also an exceptionally good substrate for the CYP1A1 enzyme. The results showing the potent and transient effect of these formylindolocarbazoles, thus emphasize their important properties as signal substances in the Ah receptor pathway. This makes the most potent compound, FICZ, a good candidate for the endogenous ligand of the Ah receptor necessary for normal development and for the basal expression of Ah receptor-dependent genes.

Base Sequence↗

PubMed1997

Human beta-migrating very low density lipoprotein induces foam cell formation in human mesangial cells.

To elucidate the mechanism of foam cell formation in the mesangial region of a kidney observed in a familial type III hyperlipoproteinemic patient presenting with diabetes mellitus and nephrotic syndrome, we have examined, in the present study, the effect of human beta-VLDL (apo E2/E2) on foam cell formation in human mesangial cells, since an increase in beta-VLDL is a characteristic feature of this patient. Human beta-VLDL (apo E2/E2) induced foam cell formation in human mesangial cells. The binding of [125I]LDL to human mesangial cells was inhibited completely by both LDL and beta-VLDL. On the other hand, the binding of [125I]beta-VLDL was completely inhibited by beta-VLDL, but partially by LDL. The LDL receptor, but not the VLDL receptor was down-regulated by accumulation of cholesteryl esters. These results suggest that human beta-VLDL (apo E2/E2)-induced foam cell formation in mesangial cells is mediated through both the LDL receptor pathway and the beta-VLDL specific pathway, in which the VLDL receptor is one of the candidates.

Blotting, Northern↗

PubMed1999

Detection of chromosomal imbalances in growth hormone-secreting pituitary tumors by comparative genomic hybridization.

Although recent molecular investigations have identified a number of genetic alterations that are associated with the development of pituitary adenomas, the exact pathogenesis mechanism of these tumors remains largely unknown. In this study, we used a genome-wide survey to detect specific genetic changes within the genome of pituitary adenomas. A series of 10 growth hormone-secreting adenomas were analyzed for their genetic imbalances on all 22 autosomes by comparative genomic hybridization (CGH). Chromosomal imbalances were detected in 8 GH-secreting adenomas, whereas 2 tumors had no detectable genetic abnormalities. Chromosome gains were more frequent than losses. Overrepresentation of whole or parts of chromosomes were detected in 5/10 (50%) in 19, 3/10 (30%) in each of 5, 9, and 22q, 2/10 (20%) in 17p12-q21, whereas DNA loss were 3/10 (30%) in 13q and 2/10 (20%) in 18. No detectable gain or loss of genetic material was observed in chromosomes 7, 8, 10, 12, 15, and 20. The findings of overrepresentation of chromosomes 5q, 9p, 17q and DNA loss of chromosome 18 were consistent with those detected in nonfunctioning adenomas (Daniely M, Aviram A, Adams EF, et al:J Clin Endocrinol Metab 83:1801-1805, 1998) suggesting that the development of pituitary tumors, at least in somatotroph and nonfunctioning adenomas, may share common pathway. Frequent amplifications in chromosomes 19 and 22q imply that candidate genes residing in these chromosomal regions may be involved in the pathogenesis of GH-secreting adenomas.

Adenoma↗

PubMed1997

Mutation analysis of 8p genes POLB and PPP2CB in bladder cancer.

The DNA polymerase beta gene (POLB), which encodes a DNA polymerase believed to be involved in short gap-filling DNA synthesis, has been mapped to the proximal region of 8p (8p12-p11), a region commonly deleted in bladder carcinoma and a wide variety of other neoplasms. Also mapped to this region (8p12-p11.2) is the gene encoding the beta isoform of the catalytic subunit of protein phosphatase 2A (PPP2CB), a major serine/threonine phosphatase thought to play a regulatory role in many cellular pathways. The known functions of these proteins make them good candidates for 8p tumor suppressor genes. To test this hypothesis, we assessed a series of bladder tumors and bladder tumor cell lines for sequence variation in POLB and PPP2CB. Single strand conformation polymorphism (SSCP) analysis and direct sequencing of POLB cDNA derived from cell lines and tumors, many with known deletions of proximal 8p, revealed one sequence variant that was shown to represent a normal sequence polymorphism. No tumor-specific sequence variants were identified. The promotor sequence in genomic DNA from tumors with 8p LOH was also screened by SSCP. Four polymorphisms were identified but no tumor-specific mutations were found. PPP2CB was analyzed by SSCP analysis of all 7 coding exons in genomic DNA of bladder tumors and cell lines. Polymorphisms were detected in exons 4 and 5 but no tumor-specific mutations were found. We conclude that these genes are unlikely to be the suppressor genes for bladder cancer targeted by deletions of chromosome arm 8p.

Carcinoma, Transitional Cell↗

PubMed2000

Evolving concepts in the pathogenesis of chronic obstructive pulmonary disease.

It is arguable that more biologic insight has been gained from the study of COPD than from any other pulmonary disorder. A vast knowledge of the biology of extracellular matrix proteins, proteinases, and proteinase inhibitors has largely stemmed from the elastase:anti-elastase hypothesis for the pathogenesis of emphysema. An equally compelling case could be made that interest in, and funding for, COPD research has been woeful, and investigators have made no significant medical breakthroughs in the treatment of this disorder, which, unfortunately, is becoming epidemic worldwide. Indeed, it cannot be argued that physicians have very little treatment to offer to the many patients with COPD. Humankind is rapidly approaching a time when all human genes will be sequenced, and genetic engineering will allow determination of the function of these proteins in vivo. Expression profiling and bioinformatics will allow clinicians to assess the spectrum of genes and proteins regulated in biologic processes, no longer limiting study to naïve candidate genes. These advances will allow investigators to decipher precise pathways of complex diseases, identify genetic and environmental interactions, and ultimately lead to specific (pre)diagnoses and rational treatment. Answers to the question as to why only a subset of smokers develop COPD will enhance the understanding of the disease process. Fortunately, there has been a resurgence of interest in COPD, led largely by the pharmaceutical industry, which has discovered the potential of this unmet need. Consequently, these state-of-the-art scientific techniques are being directly applied to COPD, lending hope for the future. Of even greater importance, the tide seems to be turning on the cigarette industry. Although difficult to imagine, perhaps cigarettes will disappear in this lifetime or at least the next generation won't be fooled by this deadly habit! Well ... the rational therapy thing could work.

Airway Obstruction↗

PubMed2003

Curly bare (cub), a new mouse mutation on chromosome 11 causing skin and hair abnormalities, and a modifier gene (mcub) on chromosome 5.

In the outcrossing of a new recessive mouse mutation causing hair loss, a new wavy-coated phenotype appeared. The two distinct phenotypes were shown to be alternative manifestations of the same gene mutation and attributable to a single modifier locus. The new mutation, curly bare (cub), was mapped to distal Chr 11 and the modifier (mcub) was mapped to Chr 5. When homozygous for the recessive mcub allele, cub/cub mice appear hairless. A single copy of the dominant Mcub allele confers a full, curly coat in cub/cub mice. Reciprocal transfer of full-thickness skin grafts between mutant and control animals showed that the skin phenotype was tissue autonomous. The hairless cub/cub mcub/mcub mice show normal contact sensitivity responses to oxazolone. The similarity of the wavy coat phenotype to those of Tgfa and Egfr mutations and the map positions of cub and mcub suggest candidate genes that interact in the EGF receptor signal transduction pathway.

Animals↗

PubMed2002

Random mutagenesis in the mouse as a tool in drug discovery.

The flood of raw information generated by large-scale data acquisition technologies in genomics, microarrays and proteomics is changing the early stages of the drug discovery process. Although many more potential drug targets are now available compared with the pre-genomics era, knowledge about the physiological context in which these targets act--information crucial to both discovery and development--is scarce. Random mutagenesis strategies in the mouse provide scalable approaches for both the gene-driven validation of candidate targets in vivo and the discovery of new physiological pathways by phenotype-driven screens.

Amino Acid Sequence↗

PubMed2006

Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome.

Velocardiofacial syndrome (VCFS) is caused by a microdeletion in chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. The catechol-O-methyltransferase (COMT), residing in the 22q11.2 microdeletion region, is a major candidate gene for genetic susceptibility to neuropsychiatric disorders in VCFS. Individuals with VCFS carrying the low-activity allele (COMTL) are expected to have the lowest possible COMT activity since they have only a single copy of the gene. We explored the possibility that COMTL is associated with psychiatric disorders commonly found in VCFS. Fifty-five unrelated individuals with VCFS underwent psychiatric evaluation and were genotyped for the COMT 158Val/Met polymorphism coding for COMT high/low-activity alleles. The COMTL allele was significantly more prevalent in VCFS subjects with attention deficit hyperactivity disorder (ADHD) (73.9% vs. 33.3%, OR 5.67, chi2=7.76, p=0.005) and obsessive-compulsive disorder (OCD) (78.6% vs. 33.3%, OR 7.33, chi2=7.24, p=0.007) than in the control group (VCFS subjects without OCD, ADHD and schizophrenia/schizoaffective (SZ/SZaff) disorder). The results of this study suggest that greatly reduced COMT activity, as expected in VCFS COMTL individuals may be a risk factor for psychiatric sequelae in this population. Future longitudinal studies focusing on additional COMT polymorphic sites and other candidate genes from the deleted region will elucidate the molecular pathways leading to schizophrenia and other psychiatric disorders in VCFS.

Adolescent↗

PubMed2006

Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation.

The accumulation of the lipofuscin fluorophores in retinal pigment epithelial (RPE) cells leads to the blinding degeneration characteristic of Stargardt disease and related forms of macular degeneration. RPE lipofuscin, including the fluorophore A2E, forms in large part as a byproduct of the visual cycle. Inhibiting visual cycle function with small molecules is required to prevent the formation of the retinotoxic lipofuscins. This in turn requires identification of rate-limiting steps in the operation of the visual cycle. Specific, non-retinoid isoprenoid compounds are described here, and shown through in both in vitro and in vivo experiments, to serve as antagonists of RPE65, a protein that is essential for the operation of the visual cycle. These RPE65 antagonists block regeneration of 11-cis-retinal, the chromophore of rhodopsin, thereby demonstrating that RPE65 is at least partly rate-limiting in the visual cycle. Furthermore, chronic treatment of a mouse model of Stargardt disease with the RPE65 antagonists abolishes the formation of A2E. Thus, RPE65 is also on the rate-limiting pathway to A2E formation. These nontoxic isoprenoid RPE65 antagonists are candidates for the treatment of forms of macular degeneration wherein lipofuscin accumulation is an important risk factor. These antagonists will also be used to probe the molecular function of RPE65 in vision.

Amides↗

PubMed1996

Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2.

The ces (for cell-death specification) genes of the nematode Caenorhabditis elegans control the cell-death fate of individual cell types and are candidates for being the regulators of an evolutionarily conserved general pathway of programmed cell death. Here we present what we believe is the first molecular characterization of a ces gene. We cloned the gene ces-2, which is required to activate programmed cell death in the sister cells of the serotoninergic neurosecretory motor (NSM) neurons, and found that ces-2 encodes a basic region leucine-zipper (bZIP) transcription factor. The CES-2 protein is most similar to members of the PAR (proline- and acid-rich) subfamily of bZIP proteins and has DNA-binding specificity like that of PAR-family proteins. An oncogenic form of the mammalian PAR-family protein, hepatic leukaemia factor (HLF), is reported to effect programmed cell death in mammalian cells. On the basis of these observations, we suggest that some CES-2/PAR family transcription factors are evolutionary conserved regulators of programmed cell death.

Amino Acid Sequence↗