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Results for “molecular pathways”

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PubMed2005

A life-long search for the molecular pathways of steroid hormone action.

The O'Malley laboratory first showed that estrogen and progesterone act in the nucleus to stimulate synthesis of specific mRNAs (ovalbumin and avidin), coding for their respective inducible proteins. The overall molecular pathway of steroid-receptor-DNA-mRNA-protein-function was then established and provided a coherent foundation for future studies of the impact of estrogen and progesterone receptors on endocrine tissue development, adult function, and in pathologies such as cancer. The lab group went on to: biochemically demonstrate ligand-induced conformational activation of progesterone and estrogen receptors, discover the concept of ligand-independent activation of steroid receptors, discover key steroid receptor coactivator intermediary coactivators for receptor function, and define the role of coactivators/corepressors in selective receptor modulator drug action and in cell homeostasis. This body of work advanced our molecular understanding of the critical role of steroid hormones in normal and abnormal physiology and also generated a base of scientific knowledge that served to further modern hormonal therapy and disease management.

Animals↗
PubMed2006

Apoptosis and molecular pathways in the seminiferous epithelium of aged and photoinhibited Syrian hamsters (Mesocricetus auratus).

Aging and short photoperiod exposure induce germ cell apoptosis in the Syrian hamster; however, the specific germ cells affected and the molecular pathways triggered have not been elucidated. We analyzed germ cell apoptosis and the expression of the Fas/Fas-L system, Bcl-2 family, and p53 in aged and photoinhibited hamsters and compared with those young maintained in natural photoperiod. Aging increased apoptosis in spermatogonia and spermatocytes, but in photoinhibited hamster testes only an increase in apoptotic spermatocytes was observed. Apoptosis was higher in aged hamsters in stages I-IV, V-VI and VII-VIII. Aging increased apoptosis of spermatogonia in stages I-IV and V-VI. Apoptotic pachytene spermatocytes were significantly higher in stages I-IV, V-VI, and VII-VIII in aging. Apoptotic preleptotene and pachytene spermatocytes were higher in aging, but no differences were observed in leptotene-zygotene. Fas-L was expressed by Sertoli cells, of young, aged, and photoinhibited hamsters. Bcl-x(L) was strongly expressed in germ cells on young hamsters and slightly in aging and after short photoperiod exposure. Spermatocytes of photoinhibited hamsters were intensively stained with Fas, Bax, Bcl-xs/L, and p53. In conclusion, aging increases apoptosis in spermatogonia and spermatocytes, depending on the stage of the seminiferous epithelium cycle, whereas after a short photoperiod exposure only an increase in apoptotic spermatocytes is observed. The results suggest that Fas, Bcl-x(L), Bax, and p53 participate in germ cell apoptosis induction after short photoperiod exposure, whereas only Bcl-x(L) is involved in aging.

Aging↗
PubMed1999

Multiple molecular pathways for fitness recovery of an RNA virus debilitated by operation of Muller's ratchet.

Repeated bottleneck passages of RNA viruses result in fitness losses due to accumulation of deleterious mutations. We have analysed the molecular events underlying fitness recovery of a highly debilitated foot- and-mouth disease virus (FMDV) clone, upon serial passage in BHK-21 cells. The debilitated clone included an unusual, internal polyadenylate extension preceding the second functional AUG initiation codon, and a number of additional mutations scattered throughout the genome. Comparison of entire genomic nucleotide sequences in the course of passaging documented that loss of the internal polyadenylate was the first event in the process of fitness recovery. Further increases of fitness were associated with very few true reversions and with the accumulation of additional mutations affecting non-coding and coding regions. Remarkably, four biological subclones of the same debilitated FMDV clone gained fitness through three separate molecular pathways regarding correction of the internal polyadenylate: (i) a true reversion to yield the wild-type sequence at the second functional AUG; (ii) a shortening of the internal polyadenylate tract; or (iii) a deletion of 69 residues spanning the site of the polyadenylate extension. The results document that an RNA virus can find multiple pathways to reach alternative high fitness peaks on the fitness landscape.

Adaptation, Physiological↗
PubMed1995

The signals and molecular pathways involved in implantation, a symbiotic interaction between blastocyst and endometrium involving adhesion and tissue invasion.

Implantation is a complex process requiring the interaction of the blastocyst, and subsequently the developing embryo with the endometrium. Initially, the detailed cellular interactions implicated in this process were defined. More recently, many signals and molecular pathways are recognized that induce, or regulate the complex series of interactions required for implantation. In this review, the cellular and molecular interactions that take place during implantation are discussed.

Animals↗
PubMed2006

Molecular pathways regulating pro-migratory effects of Hedgehog signaling.

The Hedgehog proteins play a crucial role in metazoan embryo development. Constitutive activation of the pathway is associated with multiple types of cancer. Recent experimental data suggest involvement of Hedgehog signaling in vascular remodeling, germ cell migration, and axon guidance. The molecular mechanisms underlying these effects remain elusive. Here we show that yolk sac-derived endothelial cells and embryonic fibroblasts can directly respond to the Hedgehog signal by increased migration in an in vitro scratch (wound) assay. We also identify Hedgehog transcriptional target genes in these cells, many of which participate in cell migration, axon guidance, and angiogenesis processes. Inhibition of one such molecular pathway, neuropilin-flavomonooxygenase, blocks Hedgehog-induced cell migration. These findings suggest that Hedgehog signaling directly affects embryonic endothelial and fibroblast cell migration via molecules and pathways known to regulate cell migration in response to a variety of environmental cues.

Animals↗
PubMed2005

Tools enabling the elucidation of molecular pathways active in human disease: application to Hepatitis C virus infection.

BACKGROUND: The extraction of biological knowledge from genome-scale data sets requires its analysis in the context of additional biological information. The importance of integrating experimental data sets with molecular interaction networks has been recognized and applied to the study of model organisms, but its systematic application to the study of human disease has lagged behind due to the lack of tools for performing such integration. RESULTS: We have developed techniques and software tools for simplifying and streamlining the process of integration of diverse experimental data types in molecular networks, as well as for the analysis of these networks. We applied these techniques to extract, from genomic expression data from Hepatitis C virus-infected liver tissue, potentially useful hypotheses related to the onset of this disease. Our integration of the expression data with large-scale molecular interaction networks and subsequent analyses identified molecular pathways that appear to be induced or repressed in the response to Hepatitis C viral infection. CONCLUSION: The methods and tools we have implemented allow for the efficient dynamic integration and analysis of diverse data in a major human disease system. This integrated data set in turn enabled simple analyses to yield hypotheses related to the response to Hepatitis C viral infection.

Computational Biology↗
PubMed2001

Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis.

Alterations of K- ras, p53, p16 and DPC4/Smad4 characterize pancreatic ductal cancer (PDC). Reports of inactivation of these latter two genes in pancreatic endocrine tumours (PET) suggest that common molecular pathways are involved in the tumorigenesis of pancreatic exocrine and endocrine epithelia. We characterized 112 primary pancreatic tumours for alterations in p16 and DPC4 and immunohistochemical expression of DPC4. The cases included 34 PDC, 10 intraductal papillary-mucinous tumours (IPMT), 6 acinar carcinomas (PAC), 5 solid-pseudopapillary tumours (SPT), 16 ampulla of Vater cancers (AVC) and 41 PET. All tumours were also presently or previously analysed for K- ras and p53 mutations and allelic loss at 9p, 17p and 18q. Alterations in K- ras, p53, p16 and DPC4 were found in 82%, 53%, 38% and 9% of PDC, respectively and in 47%, 60%, 25% and 6% of AVC. Alterations in these genes were virtually absent in PET, PAC or SPT, while in IPMT only K- ras mutations were present (30%). Positive immunostaining confirmed the absence of DPC4 alterations in all IPMT, SPT, PAC and PET, while 47% of PDC and 38% of AVC were immunonegative. These data suggest that pancreatic exocrine and endocrine tumourigenesis involves different genetic targets and that among exocrine pancreatic neoplasms, only ductal and ampullary cancers share common molecular events.

Adenocarcinoma, Mucinous↗
PubMed2005

Taxanes and COX-2 inhibitors: from molecular pathways to clinical practice.

The taxanes paclitaxel and docetaxel are widely used antineoplastic agents that have demonstrated significant clinical activity against a number of human tumor types. Taxanes promote microtubule polymerization and stabilization which inhibits mitosis and leads to apoptosis. Taxanes induce a number of other molecular pathways. One such example is their ability to promote transcription of the cyclo-oxygenase (COX)-2 gene and to stabilize the COX-2 messenger RNA transcript. This leads to increased production of prostaglandins, which have been implicated in tumorigenesis. Increased COX-2 activity has been associated with tumor growth, poor prognostic characteristics, and unfavorable clinical outcome; therefore, up-regulation of COX-2 might attenuate the anti-tumor effect of the taxanes. This provides the rationale for the use of COX-2 inhibitors in combination with taxanes, as this could theoretically improve the clinical efficacy of paclitaxel and docetaxel. Results from preclinical studies have generally shown enhanced anticancer activity from the addition of COX-2 inhibitors to taxane treatment. Data from Phase II clinical studies in patients with non-small cell lung cancer (NSCLC) have suggested a marginal improvement in response rate when celecoxib is added to taxane therapy when compared with historical trials in similar patient groups receiving taxane therapy. There may also be a role for COX-2 inhibitors in ameliorating some of the side effects of taxane treatment, such as fatigue, myalgia, and arthralgia. Randomized clinical trials would be needed to establish whether COX-2 inhibitors improve the therapeutic profile of docetaxel or paclitaxel in patients with solid tumors.

Animals↗
PubMed2003

Molecular pathways involved in the antineoplastic effects of calcitriol on insulinoma cells.

We have previously reported that in tumorigenic pancreatic beta-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid beta-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma beta TC(3) cells, mouse insulinoma beta TC expressing or not expressing the oncogene p53, and beta TC-tet cells overexpressing or not the antiapoptotic gene Bcl2. Our results indicate that calcitriol-induced apoptosis was dependent on the function of p53 and was associated with a biphasic increase in protein levels of transcription factor nuclear factor-kappa B. Calcitriol decreased cell viability by about 40% in p53-retaining beta TC and in beta TC(3) cells; in contrast, beta TC p53(-/-) cells were only minimally affected. Calcitriol-induced cell death was regulated by members of the Bcl-2 family of apoptosis regulatory proteins, as shown by calcitriol-induced up-regulation of proapoptotic Bax and Bak and the lack of calcitriol-induced cytotoxicity in Bcl-2-overexpressing insulinoma cells. Moreover, calcitriol-mediated arrest of beta TC(3) cells in the G(1) phase of the cell cycle was associated with the abnormal expression of p21 and G(2)/M-specific cyclin B2 genes and involved the DNA damage-inducible factor GADD45. Finally, in beta TC(3) cells, calcitriol modulated the expression of IGF-I and IGF-II genes. In conclusion, these findings contribute to the understanding of the antitumorigenic effects of calcitriol on tumorigenic pancreatic beta-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.

Animals↗
PubMed2006

Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia.

The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.

Animals↗
PubMed1999

Molecular pathways mediating activation by kainate of mitogen-activated protein kinase in oligodendrocyte progenitors.

Oligodendroglial cells express ionotropic glutamate receptors of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid hydrobromide (AMPA) and kainate (KA) subtypes. Recently, we reported that AMPA receptor agonists increased 45Ca2+ uptake and phospholipase C (PLC) activity. To further elucidate the intracellular signaling mechanisms, we examined the effects of AMPA and KA on mitogen-activated protein kinase (MAPK). KA caused a time- and concentration-dependent increase in MAPK activity (predominantly the p42mapk or ERK2) and the effect was blocked by 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), a competitive AMPA/KA receptor antagonist. Furthermore, the noncompetitive antagonists of AMPA receptor GYKI 52466 and LY 303070 prevented the actions of the agonists, indicating that the effect of KA on MAPK activation is mediated through AMPA receptors in oligodendrocyte progenitors. Chelation of extracellular Ca2+ by EDTA or inhibition of PLC with U73122 abolished MAPK activation by KA. In addition, KA-stimulated MAPK activation was reduced by the protein kinase C (PKC) inhibitors, H7 and bisindolylmaleimide, as well as downregulation of PKC by prolonged exposure to phorbol esters. The involvement of PKC in the signal transduction pathways was further supported by the ability of KA to induce translocation of PKC measured by [3H]PDBu binding. Interestingly, a wortmannin-sensitive phosphatidylinositol 3-kinase and a pertussis toxin (PTX)-sensitive G protein form part of the molecular pathways mediating MAPK activation by AMPA receptor. A specific inhibitor of MAPK kinase, PD 098059, blocked MAPK activation and reduced KA-induced c-fos gene expression. All together, these results indicate that MAPK is implicated in the transmission of AMPA signaling to the nucleus and requires extracellular Ca2+, and PLC/PKC activation.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2002

Molecular pathways of regeneration and repair after liver transplantation.

Injury to liver grafts due to cold ischemia, preservation, and reperfusion continues to be an important factor in patient outcome after liver transplantation. The development of therapeutic interventions that can limit ischemic injury, enhance recovery, and improve early graft function can have a major impact on patient morbidity. The mechanisms of hepatic preservation and reperfusion injury, the molecular pathways of graft recovery, and the cells involved remain poorly understood. With significant damage to parenchymal tissue following cold ischemic injury comes the need for replacement or repair of injured cells. In a rat liver transplant model, expression of cytokines and activation of transcription factors associated with the cell cycle resulting in cellular replication correlates with the length of cold ischemia and the degree of damage. The resident liver macrophage, the Kupffer cell, has been implicated as the primary source of inflammatory factors but may also be the source of important growth factors and cytokines that initiate cellular recovery and regeneration. Determining the source of the initiating signal is important, as manipulation of this signal can be used for therapeutic interventions in such fields as transplantation, tumor immunology, and inflammatory disease. These studies demonstrate the critical interrelation between parenchymal cells and cells of the immune system during signaling and recovery from preservation and reperfusion injury in the liver. Further defining the role of these immune cells and their products during the initiation of cellular recovery is essential for developing strategies to improve hepatocellular function after injury.

Animals↗
PubMed2005

Representations of molecular pathways: an evaluation of SBML, PSI MI and BioPAX.

MOTIVATION: Analysis and simulation of pathway data is of high importance in bioinformatics. Standards for representation of information about pathways are necessary for integration and analysis of data from various sources. Recently, a number of representation formats for pathway data, SBML, PSI MI and BioPAX, have been proposed. RESULTS: In this paper we compare these formats and evaluate them with respect to their underlying models, information content and possibilities for easy creation of tools. The evaluation shows that the main structure of the formats is similar. However, SBML is tuned towards simulation models of molecular pathways while PSI MI is more suitable for representing details about particular interactions and experiments. BioPAX is the most general and expressive of the formats. These differences are apparent in allowed information and the structure for representation of interactions. We discuss the impact of these differences both with respect to information content in existing databases and computational properties for import and analysis of data.

Computational Biology↗
PubMed1999

A molecular pathway leading to endoderm formation in zebrafish.

BACKGROUND: Several potentially important regulators of vertebrate endoderm development have been identified, including Activin-related growth factors and their receptors; transcriptional regulators encoded by the genes Mixer, Xsox17, and HNF3beta; zebrafish One-eyed pinhead (Oep), a member of the Cripto/FRL-1/Cryptic family of epidermal growth factor related proteins (EGF-CFC); and the product of the zebrafish locus casanova, which plays an essential cell-autonomous role in endoderm formation. RESULTS: Using overexpression studies and the analysis of different zebrafish mutants, we have assembled a molecular pathway that leads to endoderm formation. We report that a zebrafish Sox17 homologue is expressed during gastrulation exclusively in the endoderm and that casanova mutants lack all sox17 expression. Overexpression of mixer induces ectopic sox17-expressing cells in wild-type embryos and promotes endoderm formation in oep mutants, but does not rescue sox17 expression or endoderm formation in casanova mutants. Overexpression of a constitutively active form of the type I transforming growth factor beta (TGF-beta) receptor TARAM-A also promotes sox17 expression in wild-type and oep mutant embryos, but not in casanova mutants. We also show that the Nodal-related molecules Cyclops and Squint and the transmembrane protein Oep are essential for normal mixer expression. CONCLUSIONS: The data indicate that the following pathway leads to zebrafish endoderm formation: Cyclops and Squint activate receptors such as TARAM-A; Oep also appears to act upstream of such receptors; signals transduced by these receptors lead to the expression of mixer, Mixer then acts through casanova to promote the expression of sox17 and differentiation of the endoderm.

Amino Acid Sequence↗
PubMed2005

Unraveling the molecular pathways that regulate early telencephalon development.

The telencephalon, at the rostral end of the developing central nervous system, starts off as a sheet of neuroepithelial cells. During development, this sheet of cells becomes patterned and morphologically partitioned into areas that give rise to the adult cerebral hemispheres. How does this happen? How are telencephalic precursor cells instructed to generate myriad neural cell types in different areas and at different times as well as to change their rates of cell proliferation, differentiation, and death? The molecular pathways required for patterning the telencephalic neuroepithelium and forming the cerebral hemispheres are beginning to be unraveled.

Animals↗
PubMed1996

New insights on molecular pathways utilized by salmonella species in cell binding.

Salmonella infections are a principal source of gastroenteritis and enteric fever in a variety of animals, including humans. An essential step in the development of Salmonella pathogenesis is the entry of bacteria into non-phagocytic cells, including those that line the intestinal epithelium. As a consequence of specific cues from the host intestinal micro-environment, Salmonella entry into the intestinal epithelium is the product of a multistep process that culminates in host cell membrane ruffling, and subsequent bacterial uptake. The events that trigger the internalization event appear to require an array of bacterial secreted proteins, exemplified by the formation of bacterial surface appendages (invasomes) which are important for the induction of host-cell signal transduction pathways that lead to membrane ruffling. In addition, during intestinal disease states induced by Salmonella typhimurium, transepithelial migration of neutrophils rapidly follows attachment of the bacteria to the epithelial membrane. Current evidence indicates that the intestinal epithelium plays a key role in orchestrating the inflammatory response to surface attached S. typhimurium. In this review, we explore current insights on the molecular pathways utilized by Salmonella spp. in cell binding that are important not only in the processes of Salmonella internalization but also in the generation of signals which lead to active states of intestinal inflammation.

Animals↗
PubMed1991

Divergent molecular pathways of productive and latent infection with a virulent strain of herpes simplex virus type 1.

Mutants of herpes simplex virus (HSV) have been used to show that a variety of key genes associated with initiation of lytic infection or replication of viral DNA are not essential for establishment of latency. These observations are extended in the present study, in which a virulent strain of HSV type 1 that is not compromised in its ability to productively infect neurons under favorable conditions was used to demonstrate early divergence of molecular pathways leading to productive and latent infection. Our experimental strategy made unique use of the segmental innervation of the vertebrate trunk to study the spread of virus throughout the peripheral nervous system after inoculation of mouse flanks. Evidence of viral gene expression, including that of immediate-early genes, was transient, confined to ganglia directly innervating the inoculated skin (8th through 12th thoracic segments), and seen only at sites from which infectious virus could be recovered. In contrast, neurons containing latency-associated transcripts and reactivatable virus were more widely distributed (sixth thoracic through first lumbar segments), from which we conclude that replication-competent HSV type 1 can establish latency without initiating productive infection.

Acute Disease↗
PubMed2001

Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta. Although the etiology of PD is unknown, major biochemical processes such as oxidative stress and mitochondrial inhibition are largely described. However, despite these findings, the actual therapeutics are essentially symptomatical and are not able to block the degenerative process. Recent histological studies performed on brains from PD patients suggest that nigral cell death could be apoptotic. However, since post-mortem studies do not allow precise determination of the sequence of events leading to this apoptotic cell death, the molecular pathways involved in this process have been essentially studied on experimental models reproducing the human disease. These latter are created by using neurotoxic compounds such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or dopamine (DA). Extensive study of these models have shown that they mimick, in vitro and in vivo, the histological and/or the biochemical characteristics of PD and thus help to define important cellular actors of cell death presumably critical for the nigral degeneration. This review reports recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD and correlates them to the phenomena occurring in human disease.

Animals↗