Regulation of astrocyte cell biology by the cAMP/protein kinase A signaling pathway.
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Adenylyl Cyclases↗
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Pathogenesis of colorectal cancer.
The development of colorectal cancer has been viewed as an ordered process in which three main phases can be identified: initiation, promotion and progression. There is definite proof that stable alterations of the structure or sequence of DNA (mutations) represent the initiating event; these are followed by an uncontrolled expansion of the neoplastic clones which characterizes tumoural growth. Several classes of genes have been identified foncogenes, tumour suppressor genes and "mutator" genes) the alterations of which are important in the initiation as well as in the promotion and progression of tumours. Colorectal cancer, therefore, results from a series of genetic changes which lead to the progressive and irreversible loss of normal control of cell growth and differentiation. Available evidence is consistent with the hypothesis that there are several molecular pathways underlying the passage from normal mucosa to colorectal carcinoma, thus explaining the existence of intestinal tumours with a different biological nature, which may represent specific targets for prevention and cure. Well-defined molecular pathways have been identified for: A) sporadic colorectal cancer ("Loss of heterozygosity pathway"); B) familial adenomatous polyposis and related polyposis syndromes; C) hereditary non-polyposis colorectal cancer ("mutator genes/microsatellite instability pathway"); D) cancer developing in inflammatory bowel diseases; E) familial colorectal cancer. Thus, there is consistent and considerable evidence suggesting the existence of several biological pathways leading to the same phenotypical expression (i.e., colorectal cancer), and it is likely that additional pathways will be clarified in the future. From a practical point of view, tumours with a diverse biology might offer different and more effective preventive and curative approaches.
Colorectal Neoplasms↗
New strategy for the representation and the integration of biomolecular knowledge at a cellular scale.
The combination of sequencing and post-sequencing experimental approaches produces huge collections of data that are highly heterogeneous both in structure and in semantics. We propose a new strategy for the integration of such data. This strategy uses structured sets of sequences as a unified representation of biological information and defines a probabilistic measure of similarity between the sets. Sets can be composed of sequences that are known to have a biological relationship (e.g. proteins involved in a complex or a pathway) or that share similar values for a particular attribute (e.g. expression profile). We have developed a software, BlastSets, which implements this strategy. It exploits a database where the sets derived from diverse biological information can be deposited using a standard XML format. For a given query set, BlastSets returns target sets found in the database whose similarity to the query is statistically significant. The tool allowed us to automatically identify verified relationships between correlated expression profiles and biological pathways using publicly available data for Saccharomyces cerevisiae. It was also used to retrieve the members of a complex (ribosome) based on the mining of expression profiles. These first results validate the relevance of the strategy and demonstrate the promising potential of BlastSets.
Computational Biology↗
Human alveolar macrophage arachidonic acid metabolism.
Metabolites of arachidonic acid are potent modulators of many biological events, and their release from macrophages appears to play an important role in immune and inflammatory processes. In addition, metabolites of the cyclooxygenase or lipoxygenase pathway exhibit distinct biological effects. We used a method to determine if human alveolar macrophages (HAM) could be selectively activated to release products of cyclooxygenase or lipoxygenase pathway of arachidonic acid. HAM obtained by bronchoalveolar lavage from individuals were [3H]arachidonic acid labeled and then stimulated with lipopolysaccharide (LPS) or Ca ionophore A23187. Essentially no arachidonate metabolites were released by unstimulated cells. LPS caused dose- and time-dependent release of arachidonate and only cyclooxygenase products; no lipoxygenase products were detected, even in presence of cyclooxygenase inhibition. Metabolites released in response to LPS included thromboxane B2, prostaglandins D2, F2a, E2, and hydroxyheptadecatrienoic acid. A23187 caused a rapid release of arachidonate and 5-lipoxygenase products, leukotriene B4 and 5-hydroxyeicosatetraenoic acid; no cyclooxygenase inhibition. This demonstrates that HAM are specifically activated to release metabolites derived from cyclooxygenase or lipoxygenase pathway of arachidonic acid. Additionally, shunting down an alternate pathway is not induced by use of inhibitors of either pathway. This suggests alveolar macrophages may enhance or suppress various inflammatory or immune processes in lung, in part, by selective release of various derivatives of arachidonic acid.
Arachidonate 5-Lipoxygenase↗
Differential induction of the toll-like receptor 4-MyD88-dependent and -independent signaling pathways by endotoxins.
The biological response to endotoxin mediated through the Toll-like receptor 4 (TLR4)-MD-2 receptor complex is directly related to lipid A structure or configuration. Endotoxin structure may also influence activation of the MyD88-dependent and -independent signaling pathways of TLR4. To address this possibility, human macrophage-like cell lines (THP-1, U937, and MM6) or murine macrophage RAW 264.7 cells were stimulated with picomolar concentrations of highly purified endotoxins. Harvested supernatants from previously stimulated cells were also used to stimulate RAW 264.7 or 23ScCr (TLR4-deficient) macrophages (i.e., indirect induction). Neisseria meningitidis lipooligosaccharide (LOS) was a potent direct inducer of the MyD88-dependent pathway molecules tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 3alpha (MIP-3alpha), and the MyD88-independent molecules beta interferon (IFN-beta), nitric oxide, and IFN-gamma-inducible protein 10 (IP-10). Escherichia coli 55:B5 and Vibrio cholerae lipopolysaccharides (LPSs) at the same pmole/ml lipid A concentrations induced comparable levels of TNF-alpha, IL-1beta, and MIP-3alpha, but significantly less IFN-beta, nitric oxide, and IP-10. In contrast, LPS from Salmonella enterica serovars Minnesota and Typhimurium induced amounts of IFN-beta, nitric oxide, and IP-10 similar to meningococcal LOS but much less TNF-alpha and MIP-3alpha in time course and dose-response experiments. No MyD88-dependent or -independent response to endotoxin was seen in TLR4-deficient cell lines (C3H/HeJ and 23ScCr) and response was restored in TLR4-MD-2-transfected human embryonic kidney 293 cells. Blocking the MyD88-dependent pathway by DNMyD88 resulted in significant reduction of TNF-alpha release but did not influence nitric oxide release. IFN-beta polyclonal antibody and IFN-alpha/beta receptor 1 antibody significantly reduced nitric oxide release. N. meningitidis endotoxin was a potent agonist of both the MyD88-dependent and -independent signaling pathways of the TLR4 receptor complex of human macrophages. E. coli 55:B5 and Vibrio cholerae LPS, at the same picomolar lipid A concentrations, selectively induced the MyD88-dependent pathway, while Salmonella LPS activated the MyD88-independent pathway.
Adaptor Proteins, Signal Transducing↗
Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools.
The vast amount of protein sequence data now available, together with accumulating experimental knowledge of protein function, enables modeling of protein sequence and function evolution. The PANTHER database was designed to model evolutionary sequence-function relationships on a large scale. There are a number of applications for these data, and we have implemented web services that address three of them. The first is a protein classification service. Proteins can be classified, using only their amino acid sequences, to evolutionary groups at both the family and subfamily levels. Specific subfamilies, and often families, are further classified when possible according to their functions, including molecular function and the biological processes and pathways they participate in. The second application, then, is an expression data analysis service, where functional classification information can help find biological patterns in the data obtained from genome-wide experiments. The third application is a coding single-nucleotide polymorphism scoring service. In this case, information about evolutionarily related proteins is used to assess the likelihood of a deleterious effect on protein function arising from a single substitution at a specific amino acid position in the protein. All three web services are available at http://www.pantherdb.org/tools.
Amino Acid Substitution↗
The ubiquitin-proteasome pathway in viral infections.
The cellular biological function of the ubiquitin-proteasome pathway as a major intracellular protein degradation pathway, and as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated over the last decade. The critical role of the ubiquitin-proteasome pathway in viral pathogenesis has become increasingly apparent. Many viruses have been reported to evolve different strategies to utilize the ubiquitin-proteasome pathway for their own benefits. Here, we review the general background and function of the ubiquitin-proteasome pathway, summarize our current understanding of how viruses use this pathway to target cellular proteins, and finally, discuss the roles of this pathway in enteroviral infection, and the potential therapeutic application of proteasome inhibition in myocarditis.
Animals↗
Wnt signaling: a key regulator of bone mass.
The identification of a link between bone mass in humans and gain- [high bone mass (HBM) trait] or loss-of-function [osteoporosis pseudoglioma (OPPG) syndrome] mutations in the Wnt coreceptor lipoprotein receptor-related protein (LRP)5 or in the Wnt antagonist sclerostin (sclerosteosis, Van Buchem syndrome) has called the attention of academic and industry scientists and clinicians to the importance of this signaling pathway in skeletal biology and disease. Multiple genetic and pharmacological manipulations of Wnt signaling in mice have since then confirmed the central role of this pathway in both the establishment of peak bone mass and its maintenance throughout life. Wnt signaling appears to be located downstream of bone morphogenetic proteins (BMPs), itself induced by Hedgehog (Hh) signaling, suggesting that it is the successive recruitment of these three intracellular signaling cascades that allow the full expression of the genetic patterns that characterize the osteoblast, the cell responsible for the formation of bone.
Animals↗
Biologic role(s) of the 25(R),26-hydroxycholesterol metabolic pathway.
Expression of the gene coding for the synthesis of 25(R), 26-hydroxycholesterol in many tissues and the finding that this sterol can be the sole pathway for the production of bile acids have led to a renewed interest in this metabolic pathway. A further impetus for exploring the normal biologic roles that are served by expression of the CYP27A1 gene is the knowledge that mutations in humans are associated with accelerated atherosclerosis and with severe neurologic impairment. The molecular mechanisms governing these phenotypic expressions are not known but in light of the traditional role of steroids as ligands for receptors that regulate gene expression it seems likely that the intermediates in this pathway modulate a number of enzymatic activities that remain to be elucidated.
Animals↗
Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes.
The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.
Animals↗
MPrime: efficient large scale multiple primer and oligonucleotide design for customized gene microarrays.
BACKGROUND: Enhancements in sequencing technology have recently yielded assemblies of large genomes including rat, mouse, human, fruit fly, and zebrafish. The availability of large-scale genomic and genic sequence data coupled with advances in microarray technology have made it possible to study the expression of large numbers of sequence products under several different conditions in days where traditional molecular biology techniques might have taken months, or even years. Therefore, to efficiently study a number of gene products associated with a disease, pathway, or other biological process, it is necessary to be able to design primer pairs or oligonucleotides en masse rather than using a time consuming and laborious gene-by-gene method. RESULTS: We have developed an integrated system, MPrime, in order to efficiently calculate primer pairs or specific oligonucleotides for multiple genic regions based on a keyword, gene name, accession number, or sequence fasta format within the rat, mouse, human, fruit fly, and zebrafish genomes. A set of products created for mouse housekeeping genes from MPrime-designed primer pairs has been validated using both PCR-amplification and DNA sequencing. CONCLUSION: These results indicate MPrime accurately incorporates standard PCR primer design characteristics to produce high scoring primer pairs for genes of interest. In addition, sequence similarity for a set of oligonucleotides constructed for the same set of genes indicates high specificity in oligo design.
Animals↗
Novel urinary metabolite of d-delta-tocopherol in rats.
A novel metabolite of d-delta-tocopherol was isolated from the urine of rats given d-3,4-[3H2]-delta-tocopherol intravenously. The metabolite was collected from the urine of rats given d-delta-tocopherol in the same manner as that of the labeled compound. It was found that the metabolites consisted of sulfate conjugates. The portion of the major metabolite released with sulfatase was determined to be 2,8-dimethyl-2-(2'-carboxyethyl)-6-chromanol by infrared spectra, nuclear magnetic resonance spectra, and mass spectra. The proposed structure was confirmed by comparing the analytical results with those of a synthetically derived compound. As a result of the structural elucidation of this novel metabolite, a pathway for the biological transformation of delta-tocopherol is proposed which is different from that of alpha-tocopherol. A characteristic feature of the pathway is the absence of any opening of the chroman ring throughout the sequence.
Animals↗
FSH activates phosphatidylinositol 3-kinase/protein kinase B signaling pathway in 20-day-old Sertoli cells independently of IGF-I.
The gonadotropin FSH plays a key role in the control of Sertoli cell function. The FSH molecular mechanism of action is best recognized for its stimulation of the adenylyl cyclase/cAMP pathway. However, other signaling events have also been demonstrated in Sertoli cells. We have recently presented evidence that FSH can stimulate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathway in 20-day-old Sertoli cells. At the same time, it was proposed that in 8-day-old Sertoli cells the effects of FSH on phosphorylated PKB (P-PKB) levels can be explained by a combination of increased secretion of endogenous IGF-I, decreased IGF-binding protein-3 (IGFBP-3) production, and a synergistic action of FSH on IGF-I-dependent PI3K activation. The aim of the present study was to determine whether the effect of FSH on 20-day-old Sertoli cells is mediated by IGF-I secretion. Twenty-day-old rat Sertoli cell cultures were used. FSH stimulation produced a time-dependent increment in P-PKB levels reaching maximal values in 60-min incubations. IGF-I stimulation was also time-dependent reaching maximal values in 15-min incubations. On the other hand, stimulation of the cultures with FSH showed time-dependent inhibition in phosphorylated mitogen-activated protein kinase (P-MAPK) levels. In sharp contrast, stimulation of the cultures with IGF-I showed time-dependent increments in P-MAPK levels reaching maximal stimulus in 15-min incubations. In order to rule out an IGF-I action on FSH stimulation of P-PKB levels, the effect of a specific IGF-I antibody on the ability of both hormones to increase P-PKB levels was evaluated. As expected, the antibody inhibited IGF-I stimulation of P-PKB levels. However, simultaneous addition of an IGF-I antibody with FSH did not modify the ability of the hormone to increase P-PKB levels. The next set of experiments intended to analyze the relevance of a PI3K/PKB pathway to two biological responses of Sertoli cells to FSH and IGF-I. The PI3K inhibitor, wortmannin, dose-dependently decreased FSH-stimulated lactate and transferrin production. On the other hand, wortmannin was not able to modify the ability of IGF-I to stimulate these metabolic events. In addition, the analysis of the participation of a MAPK pathway in IGF-I regulation of Sertoli cell biological responses showed that the MAPK kinase inhibitors, PD98059 and U0126, decreased IGF-I-stimulated transferrin secretion while not modifying IGF-I-stimulated lactate levels. In summary, results obtained so far support the hypothesis that FSH action on P-PKB levels and Sertoli cell metabolism in 20-day-old animals is not mediated by autocrine regulation of an IGF-I/ IGFBP-3 axis as previously proposed in 8-day-old Sertoli cells.
Animals↗
GhDMT7-mediated DNA methylation dynamics enhance starch and sucrose metabolism pathways to confer salt tolerance in cotton.
This study provides a comprehensive analysis of the impact of DNA methylation in cotton under salt stress conditions, elucidating its effects on gene expression and biological processes. Here, we determined the structures of the DNA methylation landscape across the cotton genome subjected to salt stress using whole-genome bisulfite sequencing (WGBS) and RNA-seq methodologies. We identified 4938 differentially methylated regions (DMRs) correlated with alterations in gene expression. Salt stress induced significant shifts in DNA methylation patterns, particularly in CHH contexts, suggesting context-dependent epigenetic regulation. DMRs were found to be implicated in diverse biological processes and pathways, encompassing protein metabolism, cellular homeostasis, starch and sucrose metabolism, and plant hormone signaling, all pivotal for cotton's adaptation to salt stress. Furthermore, RNA-seq analysis confirmed the impact of DNA methylation on gene expression, uncovering 9642 salt stress-responsive differentially expressed genes (DEGs). These DEGs exhibited enrichment in pathways such as carbohydrate metabolism, cell wall synthesis, and defense response, underscoring the intricate interplay between methylation and gene regulation in stress response. Moreover, the study investigated the role of the key DNA methyltransferase gene GhDMT7 in modulating cotton's response to salt stress, revealing that its downregulation enhanced cotton's salt tolerance, potentially attributed to decreased DNA methylation levels, reduced membrane damage, and enhanced antioxidant capacity. These findings elucidate the role of DNA methylation in abiotic stress resilience and provide insights for crop improvement.
Gossypium↗
Biological ageing: a fundamental, biological link between socio-economic status and health?
Socio-economic differences in health appear to be universal but the precise pathways that link socio-economic status and health remain unclear. Differential exposure to specific risk and protective factors are often cited as, at least, partial explanations of socio-economic differences in health. However, risk factors are culturally specific and risk factor-specific models of socio-economic differences in health may be inadequate: as soon as prevailing risk factors change, so too must associated explanations of socio-economic differences in health. An alternative, risk factor-independent, model of socio-economic differences in health proposes that fundamental pathways to health and disease exist and that risk and protective factors act by feeding into these pathways. We propose that biological ageing is one such fundamental pathway to health, disease and, thus, socio-economic differences in health. Biological ageing is the progressive decline in physiological ability to meet demands, that occurs over time. It is due to the accumulation of damage at the cellular level and the rate of biological ageing is determined by both environmental and genetic factors. There is increasing evidence that many known disease risk and protective factors influence the rate of cellular damage accumulation and hence biological ageing and that the pathogenesis of some important diseases is related to biological ageing. We discuss these issues and hypothesize that socio-economic differences in health are partly a result of poor people ageing faster than rich people due to the unhealthy environments to which they are exposed.
Aged↗
The inactivation of methionine synthase in isolated rat hepatocytes by sodium nitroprusside.
Methionine synthase, the enzyme that catalyses the transfer of a methyl group from 5-methyl tetrahydrofolate to homocysteine via the cofactor methylcobalamin, is one of the two established mammalian enzymes that utilise a biologically active vitamin B-12 derivative. Through its substrates, products and downstream metabolites, methionine synthase is directly involved in the sulphur amino acid pathways, polyamine biosynthesis, biological methylations and one-carbon-unit transfers. Rat liver methionine synthase was shown to be inactivated by the nitric oxide donor sodium nitroprusside. The inactivation occurred during the treatment of isolated rat hepatocytes in a time-dependent and dose-dependent manner with an apparent IC50 value of 170 microM. Highly purified rat liver methionine synthase was inactivated in a partially irreversible manner with an apparent IC50 value of 10 microM. The inactivation has been attributed to nitric oxide released by sodium nitroprusside. Since biomolecules possessing transition state metals are targets for nitric oxide, the possibility of a nitric oxide-cobalamin interaction could explain the observed inactivation. Nitric oxide is directly involved in different aspects of liver metabolic functions both under physiological and pathological conditions like sepsis and inflammation. The nitric-oxide-induced inactivation of methionine synthase could offer a rational explanation for the cellular and cytotoxic effects of this highly reactive molecule.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway.
The diverse cellular and biological functions of the nuclear factor kappa B (NF-kappaB) pathway, together with the catastrophic consequences of its aberrant regulation, demand specific and highly regulated control of its activity. As described in this review, regulation of the NF-kappaB pathway is brought about through multiple post-translational modifications that control the activity of the core components of NF-kappaB signaling: the IkappaB kinase (IKK) complex, the IkappaB proteins and the NF-kappaB subunits themselves. These regulatory modifications, which include phosphorylation, ubiquitination, acetylation, sumoylation and nitrosylation, can vary, depending on the nature of the NF-kappaB-inducing stimulus. Moreover, they frequently have distinct, sometimes antagonistic, functional consequences and the same modification can have different effects depending on the context. Given the important role of NF-kappaB in human health and disease, understanding these pathways will not only provide valuable insights into mechanism and function, but could also lead to new drug targets and the development of diagnostic and prognostic biomarkers for many pathological conditions.
Animals↗
Design and quantitative structure-activity relationship of 3-amidinobenzyl-1H-indole-2-carboxamides as potent, nonchiral, and selective inhibitors of blood coagulation factor Xa.
A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure-activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein-ligand interactions responsible for biological affinity and selectivity. Several compounds from this series are highly potent and selective inhibitors of this important enzyme linking extrinsic and intrinsic coagulation pathways. To rationalize biological affinity and to provide guidelines for further design, all compounds were docked into the factor Xa binding site. Those docking studies were based on X-ray structures of factor Xa in complex with literature-known inhibitors. It was possible to validate those binding modes by four X-ray crystal structures of representative ligands in factor Xa, while one ligand was additionally crystallized in trypsin to rationalize requirements for selective factor Xa inhibition. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r(2) values using the leave-one-out method and repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined factor Xa binding site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. The final quantitative SAR information agrees with all experimental data for the binding topology and thus provides reasonable activity predictions for novel factor Xa inhibitors.
Amides↗