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At least 1,801 records · Page 100Linked to original sources
PubMed2005

Turning it up a Notch: cross-talk between TGF beta and Notch signaling.

Signaling through both the transforming growth factor beta (TGF beta) superfamily of growth factors and Notch play crucial roles during embryonic pattern formation and cell fate determination. Although both pathways are able to exert similar biological responses in certain cell types, a functional interaction between these two signaling pathways has not been described. Now, three papers provide evidence of both synergy and antagonism between TGF beta and Notch signaling. These reports describe a requirement for Notch signal transducers in TGF beta- and BMP-induced expression of Notch target genes, as well as in BMP-controlled cell differentiation and migration. These papers uncover a direct link between the Notch and TGF beta pathways and suggest a critical role for Notch in some of the biological responses to TGF beta family signaling.

Animals↗
PubMed2002

Comparative analysis of protein interaction networks.

Recent advances in proteomics and computational biology have lead to a flood of protein interaction data and resulting interaction networks (e.g. (Gavin et al., 2002)). Here I first analyse the status and quality of parts lists (genes and proteins), then comparatively assess large-scale protein interaction data (von Mering et al., 2002) and finally try to identify biological meaningful units (e.g. pathways, cellular processes) within interaction networks that are derived from the conservation of gene neighborhood (Snel et al., 2002). Possible extensions of gene neighborhood analysis to eukaryotes (von Mering and Bork, 2002) will be discussed.

Animals↗
PubMed2003

Human herpesvirus 7 open reading frame U12 encodes a functional beta-chemokine receptor.

Human herpesvirus 7 (HHV-7), which belongs to the betaherpesvirus subfamily, infects mainly CD4+ T cells in vitro and infects children during infancy. After the primary infection, HHV-7 becomes latent. HHV-7 contains two genes (U12 and U51) that encode putative homologs of cellular G-protein-coupled receptors. To analyze the biological function of the U12 gene, we cloned the gene and expressed the U12 protein in cells. The U12 gene encoded a calcium-mobilizing receptor for the EBI1 ligand chemokine-macrophage inflammatory protein 3beta (ELC/MIP-3beta) but not for other chemokines, suggesting that the chemokine selectivity of the U12 gene product is distinct from that of the known mammalian chemokine receptors. These studies revealed that U12 activates distinct transmembrane signaling pathways that may mediate biological functions by binding with a beta-chemokine, ELC/MIP-3beta.

Amino Acid Sequence↗
PubMed2001

The biological basis of epistasis between quantitative trait loci for flavone and 3-deoxyanthocyanin synthesis in maize (Zea mays L.).

A major weakness in our understanding of the genetic basis of complex traits has been that of defining the extent and biological basis of epistasis. Our research group has been studying the genetic control of the accumulation of maysin, a C-glycosyl flavone, in maize, Zea mays (L.), silks. Previously, we demonstrated the importance of the p1 locus as a QTL for maysin synthesis. The p1 locus often exhibits significant epistatic interactions with other loci. We developed a mapping population, (W23al x GT119)F2, specifically designed to test whether genes in an intersecting pathway might be detected as QTLs for maysin synthesis and result in epistatic interaction effects. The a1 gene is not required for the synthesis of flavones but is required for the synthesis of 3-deoxyanthocyanins, an intersecting pathway, in maize silks. The p1 locus (P < 0.0001) was a QTL for both flavones and 3-deoxyanthocyanins. The a1 locus was also highly significant (P < 0.0001) for both traits, as was the p1 x a1 epistatic interaction (P < 0.0001). Our results demonstrate that altering the flux of biochemical intermediates between pathways may be the biological basis of major QTL effects and epistatic interactions.

Alleles↗
PubMed2004

Early prediction of drug metabolism and toxicity: systems biology approach and modeling.

Many of the drug candidates that fail in clinical trials are withdrawn because of unforeseen effects of human metabolism, such as toxicity and unfavorable pharmacokinetic profiles. Early pre-clinical elimination of such compounds is important but not yet possible. An ideal system would enable researchers to make a confident elimination decision based purely on the structure of a new compound, and incorporate and use multiple pre-clinical experimental data to support such a decision. Currently available resources can be split into three categories: (i). structure-activity relationships (SAR) computational models based on compound structure; (ii). 'pattern' databases of tissue or organ response to drugs, compiled from high-throughput experiments; and (iii). 'systems biology' databases of metabolic pathways, genes and regulatory networks. In this review, we outline the advantages and drawbacks of each of these systems and suggest directions for their integration.

Animals↗
PubMed2005

Development of farnesyl transferase inhibitors: a review.

Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. The exact mechanism of action of this class of agents is, however, currently unknown. The drugs inhibit farnesylation of a wide range of target proteins, including Ras. It is thought that these agents block Ras activation through inhibition of the enzyme farnesyl transferase, ultimately resulting in cell growth arrest. In preclinical models, the farnesyl transferase inhibitors showed great potency against tumor cells; yet in clinical studies, their activity was far less than anticipated. Reasons for this disappointing clinical outcome might be found in the drug-development process. In this paper, we outline an algorithm that is potentially useful for the development of biologically active anticancer drugs. The development of farnesyl transferase inhibitors, from discovery to clinical trials, is reviewed on the basis of this algorithm. We found that two important steps of this algorithm were underestimated. First, understanding of the molecular biology of the defective pathway has mainly been focused on H-Ras activation, whereas activation of K-Ras or other farnesylated proteins is probably more important in tumorigenesis. Inhibition of farnesylation is possibly not sufficient, because geranylgeranylation might activate K-Ras and suppress the effect of farnesyl transferase inhibitors. Furthermore, a well-defined proof of concept in preclinical and clinical studies has not been achieved. Integrating the proposed algorithm in future studies of newly developed biologically active anti-cancer drugs might increase the rate of success of these compounds in patients.

Animals↗
PubMed1994

Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis.

The met proto-oncogene is a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF is a multifunctional cytokine that stimulates mitogenesis, motility, invasion, and tubulogenesis of a spectrum of epithelial and endothelial cells in culture. Using a chimeric receptor (CSF-MET), containing the extracellular domain of the colony stimulating factor-1 (CSF-1) receptor fused to the transmembrane and intracellular domain of the Met receptor, we have previously demonstrated that activation of the Met kinase domain is sufficient to mediate the motility, invasion and morphogenic signals of HGF/SF in Madin-Darby canine kidney epithelial cells (MDCK). In this study we have analyzed the role of tyrosine phosphorylation of the Met receptor in the transmission of these signals by site-directed mutagenesis of specific tyrosine residues. Mutation of two tyrosine residues (tyrosine 1234 and tyrosine 1235), involved in activation of the catalytic activity of the kinase, abrogates the biological activity of the chimera. In addition, we have identified a single noncatalytic tyrosine residue (tyrosine 1356) in the carboxyl terminus of the Met receptor, that is essential for the biological activity of the chimeric receptor. Mutation of tyrosine 1356 to a nonphosphorylatable phenylalanine residue does not affect the exogenous kinase activity of the receptor toward enolase, but it impairs the ability of the mutant protein to associate with the adaptor protein Grb2, and MDCK cells expressing this mutant fail to scatter, invade, and form branching tubules in response to CSF-1. These results support a crucial role for tyrosine 1356 in activation of signaling pathways involved in the biological activity of the Met receptor in response to HGF/SF.

Animals↗
PubMed2005

Molecularly targeted therapy in renal cell carcinoma.

Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Multiple strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. This review aims to overview the findings of recent clinical trials and clarify the development of these compounds for use in renal cell carcinoma. The authors also aim to clarify the molecular pathways implicated in renal cell carcinoma and the clinical results in metastatic renal cell carcinoma with agents targeting these pathways. The relevant literature was reviewed concerning pathways implicated in the pathophysiology of renal cell carcinoma including pathways activated secondary to von Hippel-Lindau gene inactivation and PI-3 kinase/Akt/mammalian target of rapamycin pathway activation. Therapeutic targeting based upon underlying molecular biology in renal cell carcinoma has strong rationale. Substantial clinical activity has been reported with various agents targeting these pathways, most notably with vascular endothelial growth factor-targeted therapy. However, investigation is needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.

Animals↗
PubMed2004

Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration.

We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague-Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. Both gamma counting of microdissected tissue and high resolution phosphor imaging of tissue sections showed that the tissue concentrations and distribution following intranasal administration were consistent with two routes of rapid entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages with the olfactory bulbs and rostral brain regions (e.g. anterior olfactory nucleus and frontal cortex) and the other associated with the peripheral trigeminal system connecting the nasal passages with brainstem and spinal cord regions. Intranasal administration of [125I]-IGF-I also targeted the deep cervical lymph nodes, consistent with their possible role in lymphatic drainage of both the nasal passages and the CNS. Cisternal CSF did not contain [125I]-IGF-I following intranasal administration. Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.

Administration, Intranasal↗
PubMed2005

Experimental and bioinformatic approaches for interrogating protein-protein interactions to determine protein function.

An ambitious goal of proteomics is to elucidate the structure, interactions and functions of all proteins within cells and organisms. One strategy to determine protein function is to identify the protein-protein interactions. The increasing use of high-throughput and large-scale bioinformatics-based studies has generated a massive amount of data stored in a number of different databases. A challenge for bioinformatics is to explore this disparate data and to uncover biologically relevant interactions and pathways. In parallel, there is clearly a need for the development of approaches that can predict novel protein-protein interaction networks in silico. Here, we present an overview of different experimental and bioinformatic methods to elucidate protein-protein interactions.

Animals↗
PubMed2005

Employment of microarray analysis to characterize biologic differences associated with tropism-modified adenoviral vectors: utilization of non-native cellular entry pathways.

In this study, we have applied high-density oligonucleotide microarray technology to characterize biologic changes associated with adenoviral vector-mediated target cell infection. We infected a human melanoma cell line, M21, with the tropism-modified vectors, Ad5lucRGD and Ad5/3luc1. In addition, we infected the M21 cell line with the Ad5luc1, a vector which primarily exploits the coxsackie and adenovirus receptor, as its primary native receptor. We found significant changes in gene expression of 5492 genes induced by Ad5luc1 infection, 2439 genes induced by Ad5/3luc1 infection, and 1251 genes induced by Ad5lucRGD infection, compared to uninfected cells. Among these changes in gene expression, 783 changes were common to Ad5/3luc1 and Ad5luc1 infections, 266 were common to Ad5lucRGD and Ad5luc1 infections, and 185 changes in gene expression were common to Ad5/3luc1 and Ad5lucRGD infections. Interestingly, 89 changes in gene expression were common to all the three groups, suggesting a commonly affected pathway. This analysis represents a unique application of microarray to study vector-related issues. Furthermore, these studies demonstrate the utility of microarray for characterizing the biologic sequelae of host-vector interaction.

Adenoviridae↗
PubMed2005

AKT signaling in normal and malignant cells.

AKT/protein kinase B (PKB) is a cardinal node in diverse signaling cascades important in both normal cellular physiology and various disease states. AKT signaling regulates cell proliferation and survival, cell growth (size), glucose metabolism, cell motility and angiogenesis. Aberrant regulation of these processes result in cellular perturbations considered hallmarks of cancer, and numerous studies testify to the frequent hyperactivation of AKT signaling in many human cancers. Various oncoproteins and tumor suppressors intersect the AKT signal transduction pathway and are activated or inactivated, respectively, in cancer. This issue of Oncogene Reviews includes a collection of perspectives on the normal cellular functions of various components of the AKT pathway, as well as biological consequences of alterations of these proteins as related to tumorigenesis. Two reviews focus on AKT regulation, one of which addresses various aspects of phosphoinositide metabolism, while the other emphasizes the role of AKT-interacting proteins in AKT activation. Several reviews highlight the role of major AKT substrates involved in cellular metabolism, transcription and translation; another focuses on the role of AKT signaling in epithelial-mesenchymal transition. Also included are articles on the involvement of AKT pathway deregulation in human cancer and certain hereditary cancer syndromes, as well as in murine models of cancer based on AKT pathway activation. Additional articles discuss current approaches to identify selective inhibitors of the AKT pathway.

Animals↗
PubMed2006

Transcriptional profiles in liver from rats treated with tumorigenic and non-tumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil.

Conazoles are a class of fungicides used as pharmaceutical and agricultural agents. In chronic bioassays in rats, triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland, whereas, propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. These conazoles administered in the feed to male Wistar/Han rats were found to induce hepatomegaly, induce high levels of pentoxyresorufin-O-dealkylase, increase cell proliferation in the liver, increase serum cholesterol, decrease serum T3 and T4, and increase hepatic uridine diphosphoglucuronosyl transferase activity. The goal of the present study was to define pathways that explain the biologic outcomes. Male Wistar/Han rats (3 per group), were exposed to the 3 conazoles in the feed for 4, 30, or 90 days of treatment at tumorigenic and nontumorigenic doses. Hepatic gene expression was determined using high-density Affymetrix GeneChips (Rat 230_2). Differential gene expression was assessed at the probe level using Robust Multichip Average analysis. Principal component analysis by treatment and time showed within group sample similarity and that the treatment groups were distinct from each other. The number of altered genes varied by treatment, dose, and time. The greatest number of altered genes was induced by triadimefon and propiconazole after 90 days of treatment, while myclobutanil had minimal effects at that time point. Pathway level analyses revealed that after 90 days of treatment the most significant numbers of altered pathways were related to cell signaling, growth, and metabolism. Pathway level analysis for triadimefon and propiconazole resulted in 71 altered pathways common to both chemicals. These pathways controlled cholesterol metabolism, activation of nuclear receptors, and N-ras and K-ras signaling. There were 37 pathways uniquely changed by propiconazole, and triadimefon uniquely altered 34 pathways. Pathway level analysis of altered gene expression resulted in a more complete description of the associated toxicological effects that can distinguish triadimefon from propiconazole and myclobutanil.

Animals↗
PubMed1993

Linkage of proliferative and maturational abnormalities in chronic myelogenous leukemia and relevance to treatment.

Despite recent advances in our understanding of the molecular and biological abnormalities in chronic myelogenous leukemia (CML) this new knowledge has not yet led to significant improvements in treatment. We have reviewed what is known and still unknown about the molecular and biological abnormalities in CML that may be relevant to developing improved, more selective treatment. CML originates in a multipotential stem cell due to its acquiring a highly consistent specific chromosomal translocation between chromosomes 9 and 22; this results in a fused bcr/abl gene and an abnormal 210 kDa fusion protein which has increased intrinsic protein tyrosine kinase activity compared to the normal c-abl protein. It is still unknown how p210bcr-abl alters the signal transduction pathways, but the main biological abnormality is discordant or asynchronous maturation, with the cytoplasm generally maturing more rapidly than the nucleus. The major expansion of the CML population takes place in the intermediate and later maturation compartments rather than in the stem cell or early progenitor cell compartments. The expansion occurs slowly, probably taking several years to reach a trillion or more cells, at which time clinical symptoms begin to develop. The maturing leukemic progenitors do not have an increased proliferative rate, but they undergo one or more additional divisions and also live longer than comparable normal progenitors. The earliest CML blast cell population we have been able to study has reduced ultimate proliferative capacity compared to a comparable primitive normal blast cell population. Although no quantitative stem cell assay is available, indirect evidence suggests that the CML stem cells' biological behavior may be relatively unaffected or deviate only slightly from normal. The bcr/abl gene and its fusion protein are promising targets for development of novel specific therapies, but before this can be accomplished it will be necessary to understand more completely the molecular and biochemical abnormalities and to correlate them with the biological manifestations of the disease.

Bone Marrow↗
PubMed2006

Cerebellar modulation of feeding-related neurons in rat dorsomedial hypothalamic nucleus.

Cerebellum has newly been implicated in many more nonsomatic functions other than motor control. Previous studies indicate that the cerebellum is involved in feeding regulation and that the gastric vagal nerves transmit short-term meal-related visceral signals, including cholecystokinin (CCK), into the hypothalamus. Recently, the dorsomedial hypothalamic nucleus (DMN) has been thought to play an important role in feeding control. Here we investigate whether the inputs from cerebellar interpositus nucleus (IN) can reach and converge onto single DMN neurons with some feeding-related visceral signals, including gastric vagal inputs, CCK, and blood glucose, whose concentration is closely linked to food intake. Among the 259 DMN neurons recorded, 120 (46.3%) and 169 (65.3%) responded to the cerebellar IN and gastric vagal stimulations, respectively. Within the 120 DMN neurons responsive to the cerebellar IN stimulation, 98 (81.7%) also responded to the gastric vagal stimulus, and a summation of the responses was observed further (n = 20), suggesting a convergence and interaction of cerebellar and gastric vagal inputs on the cells. Moreover, among the 98 cells receiving convergent inputs from cerebellar IN and gastric vagal nerves, 69 (70.4%) were identified to be glycemia sensitive, and 22 (68.8%) of the 32 tested neurons were also sensitive to systemic CCK. These results demonstrate that the DMN integrates somatic information forwarded by the cerebellar IN and visceral signals related to food intake, including gastric vagal, CCK and glycemia, and electrophysiologically reveal a novel cerebellohypothalamic IN-DMN pathway through which the cerebellum may actively participate in short-term feeding regulation.

Action Potentials↗
PubMed2001

A protein-protein interaction map of the Caenorhabditis elegans 26S proteasome.

The ubiquitin-proteasome proteolytic pathway is pivotal in most biological processes. Despite a great level of information available for the eukaryotic 26S proteasome-the protease responsible for the degradation of ubiquitylated proteins-several structural and functional questions remain unanswered. To gain more insight into the assembly and function of the metazoan 26S proteasome, a two-hybrid-based protein interaction map was generated using 30 Caenorhabditis elegans proteasome subunits. The results recapitulate interactions reported for other organisms and reveal new potential interactions both within the 19S regulatory complex and between the 19S and 20S subcomplexes. Moreover, novel potential proteasome interactors were identified, including an E3 ubiquitin ligase, transcription factors, chaperone proteins and other proteins not yet functionally annotated. By providing a wealth of novel biological hypotheses, this interaction map constitutes a framework for further analysis of the ubiquitin-proteasome pathway in a multicellular organism amenable to both classical genetics and functional genomics.

Animals↗
PubMed2006

Progress in in silico functional genomics: the malaria Metabolic Pathways database.

Genomic, transcriptomic and proteomic data can be turned into biologically meaningful information if they are synthesized into processes. Such amalgamation has been done for the most virulent malaria parasite Plasmodium falciparum in the Metabolic Pathways database. The dialectics of construction of metabolic pathways and other biological processes using this database is presented here. Additional features, such as links to other databases and the incorporation of transcriptomic clocks, are elucidated. Comparison of Metabolic Pathways to other similar databases is analyzed.

Animals↗
PubMed2006

Endocannabinoids in appetite control and the treatment of obesity.

Research into the endocannabinoid 'system' has grown exponentially in recent years, with the discovery of cannabinoid receptors and their endogenous ligands, such as anandamide and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of endocannabinoid transduction mechanisms, their metabolic pathways, and of the biological processes in which they are implicated. A decade of endocannabinoid studies has promoted new insights into neural regulation and mammalian physiology that are as revolutionary as those arising from the discovery of the endogenous opioid peptides in the 1970s. Thus, endocannabinoids have been found to act as retrograde signals: released by postsynaptic neurons, they bind to presynaptic heteroceptors to modulate the release of inhibitory and excitatory neurotransmitters through multiple G-protein-coupled receptor (GPCR)-linked effector mechanisms. The metabolic pathways of anandamide and 2-AG have now been been characterised in great detail, and we can anticipate that these pathways -- together with endocannabinoid uptake mechanisms -- will complement cannabinoid receptors as targets for the pharmacological analysis of the physiological functions of these substances. Specific insights into the potential role of endocannabinoid-CB1 receptor systems in central appetite control, peripheral metabolism and body weight regulation herald the clinical application of CB1 receptor antagonists in the management of obesity and its associated disorders.

Animals↗

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