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At least 361 records · Page 20Linked to original sources
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

Akt is altered in an animal model of Huntington's disease and in patients.

The insulin-like growth factor I (IGF-1)/Akt pathway plays a crucial role in Huntington's disease by phosphorylating the causative protein, polyQ-huntingtin, and abolishing its toxic properties [Humbert et al. (2002)Dev. Cell, 2, 831-837; Rangone et al. (2004)Eur. J. Neurosci., 19, 273-279]. Therefore, dysregulation of this pathway may be essential for disease progression. In the present report, we thus aimed to analyse the status of Akt in brain or in peripheral tissues in Huntington's disease. Using a genetic model of Huntington's disease in rat that reproduces neuronal dysfunction and death, we show a progressive alteration of Akt during neuronal dysfunction and prior neurodegeneration. By analysing a limited number of lymphoblasts and lymphocytes, we detected modifications of Akt in Huntington's disease patients confirming a dysregulation of Akt in the disease process. Finally, we demonstrate that during late stages of the disease, Akt is cleaved into an inactive form by caspase-3. These observations demonstrate a progressive but marked alteration of this pro-survival pathway in Huntington's disease, and further implicate it as a key transduction pathway regulating the toxicity of huntingtin.

Animals↗
PubMed2003

Genome-wide monitoring of wine yeast gene expression during alcoholic fermentation.

The transcriptome of a wine yeast was monitored throughout an alcoholic fermentation under conditions mimicking an enological environment. Major changes in gene expression occurred during fermentation, affecting more than 2000 genes, as the yeast adapted to changing nutritional, environmental and physiological conditions. The genes of many pathways are regulated in a highly coordinated manner, and genes involved in the key metabolic pathways of fermentation are strongly expressed. We showed that, during fermentation of a synthetic medium mimicking a natural must in which growth arrest was caused by nitrogen exhaustion, entry into the stationary phase triggered major transcriptional reprogramming. Many TOR target genes involved in nitrogen utilization or other functions are induced at this stage, suggesting that this signalling pathway plays a critical role in changes in gene expression in response to nitrogen depletion. Entry into stationary phase is a key physiological event and is followed by a general stress response. The superimposition of multiple stresses, including starvation and ethanol stress, gives rise to a unique stress response, involving hundreds of genes encoding proteins involved in various cellular processes, many of unknown function.

Ethanol↗
PubMed1977

Effect of diet restriction on some key enzymes tryptophan-NAD pathway in rats.

Dietary intake of rats was restricted by feeding varying amounts of a 20% protein diet. After 6 weeks of feeding, some key enzymes of the tryptophan and nicotinic acid-NAD pathway, liver nicotinamide nucleotide concentration, and urinary metabolites of tryptophan and nicotinic acid were studied. With an increase in diet restriction, liver tryptophan oxygenase (EC 1.13.1.12) activity increased. Quinolinate phosphoribosyltransferase (EC 2.4.2.a) activity, on the other hand, was found to decrease with moderate diet restriction up to 50% restriction, but increased again with more severe diet restriction in rats fed 25% of ad libitum intake. Liver nicotinate phosphoribosyltransferase (EC 2.4.2.11) activity was also observed to decrease with moderate diet restriction and did not further change when the restriction was severe while picolinate carboxylase (EC 4.1.1.45) activity increased significantly only in severe diet restriction. In rats fed 25% of ad libitum intake, urinary quinolinic acid excretion was low whereas N'-methylnicotinamide excretion was elevated. Alterations in the enzyme activities accompanied by changes in the levels of urinary metabolites, observed in the present study, suggest that the potential efficiency of conversion of tryptophan to nicotinamide nucleotides is not constant and is influenced by dietary intake.

Animals↗
PubMed2002

Biodegradation of dimethylphenols by bacteria with different ring-cleavage pathways of phenolic compounds.

The biodegradation of 3,4, 2,4, 2,3, 2,6 and 3,5-dimethylphenol in combination with phenol and p-cresol by axenic and mixed cultures of bacteria was investigated. The strains, which degrade phenol and p-cresol through different catabolic pathways, were isolated from river water continuously polluted with phenolic compounds of leachate of oil shale semicoke ash heaps. The proper research of degradation of 2,4 and 3,4-dimethylphenol in multinutrient environments was performed. The degradation of phenolic compounds from mixtures indicated a flux of substrates into different catabolic pathways. Catechol 2,3-dioxygenase activity was induced by dimethylphenols in Pseudomonas mendocina PC1, where meta cleavage pathway was functional during the degradation of p-cresol. In the case of strains PC18 and PC24 of P. fluorescens, the degradation of p-cresol occurred via the protocatechuate ortho pathway and the key enzyme of this pathway, p-cresol methylhydroxylase, was also induced by dimethylphenols. 2,4 and 3,4-dimethylphenols were converted into the dead-end products 4-hydroxy-3-methylbenzoic acid and 4-hydroxy-2-methylbenzoic acid. In the degradation of 3,4-dimethylphenol, the transient accumulation of 4-hydroxy-2-methylbenzaldehyde repressed the consumption of phenol from substrate mixtures. A mixed culture of strains with different catabolic types made it possible to overcome the incompatibilities at degradation of studied substrate mixtures.

Biodegradation, Environmental↗
PubMed2002

A giant protease with a twist: the TPP II complex from Drosophila studied by electron microscopy.

Tripeptidyl peptidase II (TPP II) is an exopeptidase of the subtilisin type of serine proteases that is thought to act downstream of the proteasome in the ubiquitin-proteasome pathway. Recently, a key role in a pathway parallel to the ubiquitin-proteasome pathway has been ascribed to TPP II, which forms a giant protease complex in mammalian cells. Here, we report the 900-fold purification of TPP II from Drosophila eggs and demonstrate via cryo-electron microscopy that TPP II from Drosophila melanogaster also forms a giant protease complex. The presented three-dimensional reconstruction of the 57 x 27 nm TPP II complex at 3.3 nm resolution reveals that the 150 kDa subunits form a superstructure composed of two segmented and twisted strands. Each strand is 12.5 nm in width and composed of 11 segments that enclose a central channel.

Aminopeptidases↗
PubMed2003

Purification of the formate-tetrahydrofolate ligase from Methylobacterium extorquens AM1 and demonstration of its requirement for methylotrophic growth.

The serine cycle methylotroph Methylobacterium extorquens AM1 contains two pterin-dependent pathways for C(1) transfers, the tetrahydrofolate (H(4)F) pathway and the tetrahydromethanopterin (H(4)MPT) pathway, and both are required for growth on C(1) compounds. With the exception of formate-tetrahydrofolate ligase (FtfL, alternatively termed formyl-H(4)F synthetase), all of the genes encoding the enzymes comprising these two pathways have been identified, and the corresponding gene products have been purified and characterized. We present here the purification and characterization of FtfL from M. extorquens AM1 and the confirmation that this enzyme is encoded by an ftfL homolog identified previously through transposon mutagenesis. Phenotypic analyses of the ftfL mutant strain demonstrated that FtfL activity is required for growth on C(1) compounds. Unlike mutants defective for the H(4)MPT pathway, the ftfL mutant strain does not exhibit phenotypes indicative of defective formaldehyde oxidation. Furthermore, the ftfL mutant strain remained competent for wild-type conversion of [(14)C]methanol to [(14)C]CO(2). Collectively, these data confirm our previous presumptions that the H(4)F pathway is not the key formaldehyde oxidation pathway in M. extorquens AM1. Rather, our data suggest an alternative model for the role of the H(4)F pathway in this organism in which it functions to convert formate to methylene H(4)F for assimilatory metabolism.

Alleles↗
PubMed2004

A nuclear function for armadillo/beta-catenin.

The Wnt signaling pathway provides key information during development of vertebrates and invertebrates, and mutations in this pathway lead to various forms of cancer. Wnt binding to its receptor causes the stabilization and nuclear localization of beta-catenin. Nuclear beta-catenin then functions to activate transcription in conjunction with the transcription factor TCF. A recent report has challenged this basic precept of the Wnt signaling field, arguing that the nuclear localization of beta-catenin may be unrelated to its function and that beta-catenin functions at the plasma membrane to activate this signaling pathway. Here we present evidence that the pathway in fact does depend on the nuclear localization of beta-catenin. We reexamine the functionality of various truncations of beta-catenin and find that only the most severe truncations are true signaling-null mutations. Further, we define a signaling-null condition and use it to show that membrane-tethered beta-catenin is insufficient to activate transcription. We also define two novel loss-of-function mutations that are not truncations, but are missense point mutations that retain protein stability. These alleles allow us to show that the membrane-bound form of activated beta-catenin does indeed depend on the endogenous protein. Further, this activity is dependent on the presence of the C-terminus-specific negative regulator Chibby. Our data clearly show that nuclear localization of beta-catenin is in fact necessary for Wnt pathway activation.

Alleles↗
PubMed1993

Androgenic regulation of glycolytic and HMP pathway in epididymis and vas deferens of rhesus monkey.

The androgenic regulation of the eleven enzymes of glycolytic pathway and two key enzymes of HMP pathway was studied in the initial segment, caput, corpus and cauda regions of the epididymis and in the vas deferens of rhesus monkey. The specific activities of enzymes were expressed as units of activity per mg DNA. Results in control animals indicate a marked difference in energy metabolism of epididymis and vas deferens. However, the epididymal duct itself did not show much regional variation in enzyme activities along its length. All the enzymes of the two pathways studied showed significant reduction after castration, the regulatory enzymes being affected more severely. On treatment with exogenous dihydrotestosterone, most of these enzymes showed stimulation in castrated monkeys, but none of them could be restored to normal level. The stimulation of these enzymes on treatment with exogenous dihydrotestosterone varied along the epididymal duct itself being maximum in the initial segment and minimum in the cauda region. The changes in the vas deferens were less marked as compared to the epididymis following castration and androgen replacement.

Animals↗
PubMed1992

Adenovirus E1A targets key regulators of cell proliferation.

Studies of E1A support the notion that small DNA tumour viruses target cellular pathways at key points that are amenable to regulation. In the case of E1A, these targets appear to be points of control of cellular proliferation and, in particular, proteins that regulate the progression of cells from G0 and G1 phases of the cell cycle into the S phase. In several cases, recent studies have identified complexes between the viral targets and other cellular proteins. These interactions may provide insight not only into the mechanism of E1A mediated transformation but also into the control of proliferation in normal cells.

Adenovirus Early Proteins↗
PubMed2026

Functional convergence of rTCA-related carbon-fixation potential and biochemical residue accumulation in seagrass sediments.

Seagrass meadows are globally significant blue carbon ecosystems, yet the microbial and biochemical mechanisms driving sediment organic carbon (SOC) accumulation remain poorly understood. To address this, we employed an integrated approach combining metagenomic sequencing, biochemical assays, and structural equation modeling to investigate carbon cycling in the seagrass and adjacent unvegetated sediments of Swan Lake, China. A total of 115,179 carbon fixation genes and 119,615 decomposition genes were identified, revealing distinct microbial community structures among the habitats. Seagrass sediments harbored more diverse carbon-fixing (CFMs) and decomposing microorganisms (CDMs), with 83 medium-to high-quality metagenome-assembled genomes (MAGs) recovered. While neutral community model analysis indicated that stochastic processes predominantly governed community assembly, functional analyses highlighted specific drivers of sequestration. The reductive tricarboxylic acid (rTCA) cycle emerged as the dominant carbon fixation pathway, with key genes (e.g., aclA, korA) showing strong positive correlations with SOC. Conversely, decomposition pathways for starch and lignin were negatively associated with SOC. Furthermore, seagrass sediments exhibited elevated concentrations of total amino sugars (TAS) and lignin phenols (TLP), which linked significantly to carbon fixation rather than decomposition. PLS-SEM revealed statistically significant associations among seagrass traits, environmental variables, microbial carbon-fixation potential, biochemical residue pools, and SOC, supporting a mechanistic pathway in which enhanced microbial functional potential drives the accumulation of recalcitrant biochemical residues, thereby facilitating long-term carbon retention in sediments. These findings emphasize the pivotal role of microbial anabolism and the accumulation of biosynthetic residues in sediment carbon storage, suggesting a functional convergence in seagrass-driven carbon sinks.

Metagenomics↗
PubMed2004

Regulation of mating and pathogenic development in Ustilago maydis.

The plant pathogenic fungus Ustilago maydis induces disease only in its dikaryotic stage that is generated after mating. This process involves coordinated cAMP and mitogen-activated protein kinase signalling to regulate transcriptional as well as morphological responses. Among the induced products is the key regulator for pathogenic development. Recent advances identified crucial nodes that interconnect these pathways. The key regulator orchestrates a complex transcriptional cascade, the components of which have been uncovered by genomic strategies. This is complemented by insights into organization, dynamics and function of the cytoskeleton, which begin to establish the links between signalling, intracellular transport processes and morphology.

Fungal Proteins↗
PubMed1999

Ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas.

The identification of mutations in Hedgehog (HH) pathway genes in some basal cell carcinomas (BCC) and the detection of HH pathway dysregulation in almost all BCC confirms the importance of this developmental regulatory pathway in human BCC tumorigenesis. Moreover, the occurrence of UVB signature mutations in key HH pathway genes in BCC provides the first genetic evidence that UV radiation (UVR) may be the principal mutagen involved in BCC tumorigenesis. We review herein current advances in the understanding of the role of the HH pathway in BCC tumorigenesis including transgenic and knock-out animal models of HH pathway dysregulation. Furthermore, we summarize abnormalities in other tumor suppressors and oncogenes including ras and p53 and evidence for interactions between these regulatory genes and the HH pathway.

Animals↗
PubMed2006

Altered expression of the Smad signalling pathway: implications for COPD pathogenesis.

Pulmonary emphysema, as a feature of chronic obstructive pulmonary disease (COPD), is characterised by destruction of alveolar tissue. The present authors previously demonstrated reduced decorin expression in the peribronchial area of COPD patients, reflecting an altered extracellular matrix (ECM) modulation. Decorin transcription is regulated by the transforming growth factor (TGF)-beta-Smad pathway, the key intracellular signal route for initiation of ECM component gene transcription. Whether this pathway is aberrantly expressed in COPD is not known. An immunohistochemical study was performed to compare protein expression of TGF-beta1 and TGF-beta receptors, Smad 2, 3, 4 and 7, and decorin in lung tissue of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II and IV COPD patients and controls. Epithelial expression of the inhibitory Smad 7 was significantly lower in patients with GOLD stages II and IV than in controls, with other Smad protein expressions being similar in the groups. The expression of TGF-beta1 and TGF-beta receptor type I was significantly lower in stage II patients. Decorin staining of the adventitia and alveolar walls was significantly reduced in COPD stage IV. In conclusion, the transforming growth factor-beta-Smad pathway is aberrantly expressed in chronic obstructive pulmonary disease patients, implying an abnormal tissue repair ultimately resulting in reduced decorin production. The results of the present study contribute to better understanding of the pathogenesis of emphysema and the airway fibrosis observed in chronic obstructive pulmonary disease patients.

Adult↗
PubMed1998

Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation.

Transforming growth factor-beta (TGF-beta) represents an evolutionarily conserved family of secreted factors that mobilize a complex signaling network to control cell fate by regulating proliferation, differentiation, motility, adhesion, and apoptosis. TGF-beta promotes the assembly of a cell surface receptor complex composed of type I (T beta RI) and type II (T beta RII) receptor serine/threonine kinases. In response to TGF-beta binding, T beta RII recruits and activates T beta RI through phosphorylation of the regulatory GS-domain. Activated T beta RI then initiates cytoplasmic signaling pathways to produce cellular responses. SMAD proteins together constitute a unique signaling pathway with key roles in signal transduction by TGF-beta and related factors. Pathway-restricted SMADs are phosphorylated and activated by type I receptors in response to stimulation by ligand. Once activated, pathway-restricted SMADs oligomerize with the common-mediator Smad4 and subsequently translocate to the nucleus. Genetic analysis in Drosophila melanogaster and Caenorhabditis elegans, as well as T beta RII and SMAD mutations in human tumors, emphasizes their importance in TGF-beta signaling. Mount ng evidence indicates that SMADs cooperate with ubiquitous cytoplasmic signaling cascades and nuclear factors to produce the full spectrum of TGF-beta responses. Operating independently, these ubiquitous elements may influence the nature of cellular responses to TGF-beta. Additionally, a variety of regulatory schemes contribute temporal and/or spatial restriction to TGF-beta responses. This report reviews our current understanding of TGF-beta signal transduction and considers the importance of a cooperative signaling paradigm to TGF-beta-mediated biological responses.

Animals↗
PubMed1998

Wnt signaling stabilizes the dual-function protein beta-catenin in diverse cell types.

The Wnt proteins constitute a large family of secreted signaling factors that performed a wide variety of inductive and regulatory functions in embryonic and postnatal development. In mammals, these include crucial roles in morphogenesis of the central nervous system, kidneys, limbs, and mammary glands. In recent years, much progress has been made in identifying components of the intracellular Wnt-1 signal transduction pathway through studies in Drosophila, C. elegans, Xenopus, and mammalian systems. Several features of this pathway are remarkably well conserved in evolution. A key component of the Wnt pathway is the cytoplasmic protein beta-catenin, whose stability is increased as a result of Wnt signaling. Although morphological effects of Wnt-1 in cell culture are seen in only a limited number of cell lines, we show here that responsiveness to Wnt-1 at the biochemical level is a common property of both epithelial and mesenchymal cells. The increased abundance of beta-catenin may have at least two functional consequences, depending on the subcellular localization of the protein. In some cell lines that respond to Wnt-1, there is a significant increase in the beta-catenin fraction associated with the plasma membrane, where the protein acts as a component of cell-cell adhesive junctions. In other cell types, the major effect of Wnt signaling is an increase in the cytosolic pool of beta-catenin. Increased abundance of this pool has recently been correlated with entry of beta-catenin into the nucleus, where the protein forms complexes with Tcf transcription factors and is thought to modulate the expression of specific genes. The dual consequences of Wnt signaling on cell adhesion and/or gene expression provide at least two potential mechanisms by which this key pathway can function in the regulation of morphogenesis.

Animals↗
PubMed2006

PP2C family members play key roles in regulation of cell survival and apoptosis.

Although unlimited proliferation of cancer cells is supported by multiple signaling pathways involved in the regulation of proliferation, survival, and apoptosis, the molecular mechanisms coordinating these different pathways to promote the proliferation and survival of cancer cells have remained unclear. SAPK and integrin-ILK signaling pathways play key roles in the promotion of apoptosis and cell proliferation/survival, respectively. Studies of TNFalpha- and H2O2-induced apoptosis revealed that ASK1, a component of the SAPK system, mediates the TNFalpha and H2O2 signaling of apoptosis. ASK1 is activated by autophosphorylation of a specific threonine residue (T845) following TNFalpha stimulation. Our recent studies indicate that PP2Cepsilon, a member of the PP2C family, associates with and inactivates ASK1 by dephosphorylating T845. In contrast, PP2Cdelta/ILKAP, a second PP2C family member, activates ASK1 by enhancing cellular phosphorylation of T845. PP2Cdelta/ILKAP also forms a complex with ILK1 to inhibit the GSK3beta-mediated integrin-ILK1 signaling in vivo, inhibiting cell cycle progression. These observations raise the possibility that PP2Cdelta/ILKAP acts to control the cross-talk between integrin-induced and TNFalpha-induced signaling pathways, inhibiting the former and stimulating the latter, thereby inhibiting proliferation and survival and promoting the apoptosis of cancer cells.

Apoptosis↗
PubMed2003

IkappaBalpha and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFkappaB pathways.

Notch and NFkappaB pathways are key regulators of numerous cellular events such as proliferation, differentiation, or apoptosis. In both pathways, association of effector proteins with nuclear corepressors is responsible for their negative regulation. We have previously described that expression of a p65-NFkappaB mutant that lacks the transactivation domain (p65DeltaTA) induces cytoplasmic translocation of N-CoR leading to a positive regulation of different promoters. Now, we show that cytoplasmic sequestration of p65 by IkappaBalpha is sufficient to both translocate nuclear corepressors SMRT/N-CoR to the cytoplasm and upregulate transcription of Notch-dependent genes. Moreover, p65 and IkappaBalpha are able to directly bind SMRT, and this interaction can be inhibited in a dose-dependent manner by the CREB binding protein (CBP) coactivator and after TNF-alpha treatment, suggesting that p65 acetylation is modulating this interaction. In agreement with this, TNF-alpha treatment results in downregulation of the Hes1 gene. Finally, we present evidence on how this mechanism may influence cell differentiation in the 32D myeloid progenitor system.

3T3 Cells↗