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Results for “Candidate pathways”

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PubMed2001

Neural control of muscle relaxation in echinoderms.

Smooth muscle relaxation in vertebrates is regulated by a variety of neuronal signalling molecules, including neuropeptides and nitric oxide (NO). The physiology of muscle relaxation in echinoderms is of particular interest because these animals are evolutionarily more closely related to the vertebrates than to the majority of invertebrate phyla. However, whilst in vertebrates there is a clear structural and functional distinction between visceral smooth muscle and skeletal striated muscle, this does not apply to echinoderms, in which the majority of muscles, whether associated with the body wall skeleton and its appendages or with visceral organs, are made up of non-striated fibres. The mechanisms by which the nervous system controls muscle relaxation in echinoderms were, until recently, unknown. Using the cardiac stomach of the starfish Asterias rubens as a model, it has been established that the NO-cGMP signalling pathway mediates relaxation. NO also causes relaxation of sea urchin tube feet, and NO may therefore function as a 'universal' muscle relaxant in echinoderms. The first neuropeptides to be identified in echinoderms were two related peptides isolated from Asterias rubens known as SALMFamide-1 (S1) and SALMFamide-2 (S2). Both S1 and S2 cause relaxation of the starfish cardiac stomach, but with S2 being approximately ten times more potent than S1. SALMFamide neuropeptides have also been isolated from sea cucumbers, in which they cause relaxation of both gut and body wall muscle. Therefore, like NO, SALMFamides may also function as 'universal' muscle relaxants in echinoderms. The mechanisms by which SALMFamides cause relaxation of echinoderm muscle are not known, but several candidate signal transduction pathways are discussed here. The SALMFamides do not, however, appear to act by promoting release of NO, and muscle relaxation in echinoderms is therefore probably regulated by at least two neuronal signalling systems acting in parallel. Recently, other neuropeptides that influence muscle tone have been isolated from the sea cucumber Stichopus japonicus using body wall muscle as a bioassay, but at present SALMFamide peptides are the only ones that have been found to have a direct relaxing action on echinoderm muscle. One of the Stichopus japonicus peptides (holothurin 1), however, causes a reduction in the magnitude of electrically evoked muscle contraction in Stichopus japonicus and also causes 'softening' of the body wall dermis, a 'mutable connective tissue'. It seems most likely that this effect of holothurin 1 on body wall dermis is mediated by constituent muscle cells, and the concept of 'mutable connective tissue' in echinoderms may therefore need to be re-evaluated to incorporate the involvement of muscle, as proposed recently for the spine ligament in sea urchins.

Amino Acid Sequence↗

PubMed2001

WNT pathway and mammary carcinogenesis: loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type.

Secreted Frizzled-related protein 1 (SFRP1) encodes a member of a protein family that contains a cysteine-rich domain similar to the WNT-binding site of Frizzled receptors and regulates the WNT pathway. The WNT pathway is frequently altered in human cancers. We have defined the pattern of SFRP1 mRNA expression in the progression of breast cancer. We show that SFRP1 is expressed in the epithelial component of normal breast, in the in situ component of ductal carcinomas and is lost in more than 80% of invasive breast carcinomas except the medullary type. Loss of SFRP1 expression is correlated with the presence of hormonal receptors. Conversely, the maintenance of SFRP1 in carcinomas is correlated with the presence of lymphoplasmocytic stroma. No significant association was observed between SFRP1 status and the level of apoptosis in tumoral cells.

Adult↗

PubMed2005

Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk.

BACKGROUND: As cellular proliferation is central to the carcinogenic process, pathways that regulate proliferation may be important. Therefore, genes in the insulin and the insulin-like growth factor signaling pathways are plausible candidates for susceptibility genes for prostate cancer. We hypothesized that functional polymorphisms in INS, IRS1, IRS2, and IGF1 may be associated with prostate cancer. METHODS: We studied 199 incident prostate cancer cases and 267 age-matched controls. Genotyping was performed for the INS +1127 Ins-PstI, IRS1 G972R, IRS2 G1079D, and the IGF1 CA-repeat polymorphisms. Outcomes were prostate cancer, Gleason score, and AJCC stage. RESULTS: The IRS1 G972R GR/RR genotypes were associated with a significant 2.8-fold increased risk for prostate cancer (95% CI 1.5-5.1, P = 0.0007). The other variants were not significantly associated with prostate cancer. The IRS1 G972R GR/RR genotypes were also significantly associated with more advanced Gleason score (P = 0.001) and AJCC stage (P = 0.004). CONCLUSIONS: These results support a role of the insulin and/or insulin-like growth factor pathways in the etiology of prostate cancer.

Adult↗

PubMed2006

Genomic view of systemic autoimmunity in MRLlpr mice.

MRLlpr mice develop spontaneous systemic autoimmunity with many hallmarks of the human disease systemic lupus erythematosus. Although a variety of genes have been implicated in this model, disease pathogenesis is still poorly understood. In an effort to identify novel genes and pathways, we performed genome-wide mRNA expression analysis in the spleens and kidneys of MRLlpr mice throughout the disease course. Samples were collected from cohorts of C57BL/6, MRL+/+ and MRLlpr mice, and profiled by flow cytometry and gene expression microarrays. Serum autoantibodies and renal pathology were studied in parallel. We identified 236 genes in MRLlpr spleen that showed significant threefold or greater changes in expression between 6 and 20 weeks. Of interest, a number of interferon-responsive genes were expressed early, and remained dysregulated throughout the disease course. Many chemokines, cell surface proteins, transcription factors and cytokines, including IFN-gamma, also showed altered expression as disease progressed. Analysis of kidneys indicated the presence of severe inflammation that coincided with evidence for changes in kidney function and elevated expression of IFN-inducible genes, complement components and antigen presentation genes. These data provide a unique genomic view of the progression to fatal autoimmunity in MRLlpr mice, and provide new candidate genes and pathways to explore.

Animals↗

PubMed2002

PRL signal transduction in the epithelial compartment of rat prostate maintained as long-term organ cultures in vitro.

Using long-term organ cultures of rat prostate tissue explants, we previously demonstrated that PRL both stimulates proliferation and acts as an androgen-independent suppressor of apoptosis in prostate epithelial cells, leading to epithelial hyperplasia. In this work we delineate intracellular signaling molecules activated by PRL in prostate tissue to identify candidate signaling proteins that are responsible for maintaining survival and proliferation of prostate epithelium in androgen-deprived growth environment. We now show that signal transducer and activator of transcription-5a (Stat5a) and Stat5b become tyrosine phosphorylated in response to PRL stimulation in rat prostate using prostate organ culture as an experimental model. Stat5 was translocated to the nuclei of epithelial cells of prostate tissue as demonstrated by immunohistochemistry. Furthermore, EMSA showed PRL-inducible binding of Stat5a homodimers and Stat5a/5b heterodimers to the PRL response element of the beta-casein gene promoter. Signaling molecules Stat3, Stat1, MAPK, or protein kinase B, which can be activated by PRL in other target cells, were not activated by PRL in prostate tissue. Furthermore, we show that Stat5a and Stat5b are continuously phosphorylated in rat prostate in vivo, although they are expressed to varying degree in separate lobes of rat prostate. Collectively, our results suggest that PRL signaling in rat prostate tissue is primarily transduced via Stat5a and Stat5b. The Stat5 pathway represents one candidate signaling mechanism, used by PRL and possibly other growth factors and cytokines, that supports the viability of prostate epithelial cells during long-term androgen deprivation.

Animals↗

PubMed1999

From genome to aetiology in a multifactorial disease, type 1 diabetes.

The common autoimmune disease type 1 diabetes provides a paradigm for the genetic analysis of multifactorial disease. Disease occurrence is attributable to the interaction with the environment of alleles at many loci interspersed throughout the genome. Their mapping and identification is difficult because the disease-associated alleles occur almost as commonly in patients as in healthy individuals; even the highest-risk genotypes bestow only modest risks of disease. The identification of common quantitative trait loci (QTL) in autoimmune disease and in other common disorders, therefore, requires a very close marriage of genetics and biology. Two QTLs have been identified in human type 1 diabetes: the major histocompatibility complex HLA class II loci and a promoter polymorphism of the insulin gene. The evidence for their primary roles in disease aetiology demonstrates the necessity of combined studies of genetics and biology. Their functions and interaction underpin an emerging picture of the basic causes of the disease and direct analyses towards other candidate genes and pathways. The genetic tools used for QTL identification include transgenesis and gene knockouts, whole genome scanning for linkage, mouse congenic strains, linkage disequilibrium mapping, and the establishment of ancestral haplotypes among disease-associated chromosomes.

Alleles↗

PubMed2005

Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2).

We report a possible association between autism in our sample and a recently described brain-expressed tryptophan hydroxylase gene (TPH2). The well-replicated involvement of the serotonin neurotransmitter system in autism has stimulated interest in many genes in the serotonin pathway as possible candidates for mutations leading to autism susceptibility. Serotonin synthesis is controlled by the rate-limiting enzyme tryptophan hydroxylase. A mouse study of the original tryptophan hydroxylase gene (TPH1) and the new isoform (TPH2) showed that while TPH1 is primarily expressed peripherally, TPH2 is found exclusively in brain tissue. We searched for human sequence variants in 6,467 nucleotides covering all 11 exons of TPH2, and also 248 nucleotides upstream of the start codon, and 935 nucleotides downstream of the stop codon. Eighteen variants were characterized in 88 subjects with autism studied at our two centers, and 95 unrelated control subjects. Using a model-free association method and empirical P value estimation, two variants showed frequency differences between autism and control subjects (P = 0.01 for a T-G variant in intron 1, and P = 0.02 for a A-T variant in intron 4). A haplotype including these variants showed slightly increased significance (P = 0.005). Further investigation of clinical phenotypes showed a possible association between presence of the variants at these two SNPs and higher scores on the Autism Diagnostic Interview (ADI) domain describing repetitive and stereotyped behaviors (P = 0.007). We conclude that TPH2 may play a modest role in autism susceptibility, perhaps relating specifically to repetitive behaviors, pending replication of this result.

Autistic Disorder↗

PubMed2004

A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population.

OBJECTIVE: In the era of postgenomic research, linkage- and association-based strategies are beginning to reveal novel complex disease genes. Using such an approach, a functional haplotype of the peptidylarginine deiminase 4 gene (PADI4) has recently been identified as a gene conferring susceptibility to rheumatoid arthritis (RA) in a Japanese population. In the present study, we investigated the association of single-nucleotide polymorphisms (SNPs) in the PADI4 gene with RA in a UK population. METHODS: Association with 4 exonic SNPs (padi4_89*G/A, padi4_90*T/C, padi4_92*G/C, and padi4_104*T/C), mapping to the PADI4 gene and defining a haplotype previously reported to be associated with RA, was investigated. Genotyping was performed using 5' allelic discrimination assays. Estimated haplotypes were generated using the expectation-maximization algorithm, and frequencies of the SNPs and haplotypes were compared between unrelated Caucasian RA patients from the UK (n = 839) and population controls (n = 481). RESULTS: Allele frequencies for the 4 SNPs in the UK population were similar to those reported in the Japanese control population, but none of these was associated with RA. As in the Japanese population, the SNPs in the UK population defined 2 major haplotypes, but neither was associated with RA (P = 0.79). CONCLUSION: A PADI4 susceptibility haplotype associated with RA in a Japanese population is not associated with RA in a UK population. Other genes involved in the citrullinating pathway remain strong candidate RA-susceptibility genes and require further investigation.

Adult↗

PubMed1989

Histochemistry of acetylcholinesterase and immunocytochemistry of an acetylcholine receptor-like antigen in the brain of the honeybee.

A histochemical staining method for acetylcholinesterase (AChE) and an antiserum raised against nicotinic acetylcholine receptors (AChR) of locust nervous tissue were applied in order to reveal certain candidates of cholinergic pathways in the brain of the honeybee. The AChE staining marked layers in the optic lobes, fibers connecting the two brain hemispheres, and fiber tracts as well as soma clusters within the protocerebrum. The calycal input regions of the mushroom bodies were labelled, whereas the intrinsic Kenyon cells showed no staining. Although the antennal afferents projecting into the dorsal lobe showed strong AChE activity, projections into the antennal lobe showed rather weak staining. Application of the antiserum against the AChR showed immunoreactivity in neuropiles, tracts, somata, and the antennal nerve. The immunoreactivity of the optic lobes coincided with the banding pattern of the AChE staining. A particularly striking overlap of AChR immunoreactivity and AChE staining was found in the lip neuropile of the mushroom bodies, which would suggest a cholinergic input into this neuropile via fibers of the median antennoglomerular tract. Because the antiserum against locust AChR binds in neuropiles displaying AChE activity, we conclude that this antiserum also cross-reacts with the bee's receptor. This interpretation is supported by experiments showing alpha-bungarotoxin (alpha-BTX) binding sites in some areas of strong immunoreactivity.

Acetylcholinesterase↗

PubMed1995

Sphingomyelin-ceramide turnover in CD28 costimulatory signaling.

When the CD28 membrane glycoprotein of T cells binds to its ligand, a signal is transmitted that is required for T cell receptor-induced proliferation and cytokine secretion: T cells are not stimulated by the CD28 signal alone. Ligation of CD28 initiated sphingomyelin hydrolysis and generated ceramide. Treatment of T cells with either exogenous sphingomyelinase or a cell-permeable ceramide analogue. C6-ceramide, mimicked the CD28 signal by inducing T cell proliferation and interleukin-2 gene transcription. Stabilization of interleukin-2 mRNA was also observed in C6-ceramide-treated cells. Thus, the sphingomyelin-ceramide pathway is a candidate for mediating the costimulatory signal.

Animals↗

PubMed2004

CYLD mutation causes multiple familial trichoepithelioma in three Chinese families.

Multiple familial trichoepithelioma (MFT) and familial cylindromatosis are two clinically distinct cancer syndromes. MFT patients developed mostly trichoepithelioma in the face while cylindromatosis patients developed cylindromas predominantly (approximately 90%) on the head and neck. However, multiple familial trichoepithelioma is occasionally associated with familial cylindromatosis while cylindromatosis patients can also develop trichoepithelioma. This has led to the speculation that the 2 types of dermatoses may be caused by dysfunction of a common pathway. Previously, a candidate MTF locus has been mapped to 9p21 while disease gene for familial cylindromatosis, the CYLD gene located on 16q21-13 has been identified. Here, we show that mutations in the CYLD gene are also the genetic basis for three different Chinese families with MFT. Sequence analysis reveal a single nucleotide deletion, c.1462delA (P.Ile488fsX9) in exon 9, a nonsense mutation, c.2128C>T (p. Gln710X) in exon 17, and a missense mutation, c.2822A>T (p. Asp941Val) in exon 21 in each of the three families respectively. This provides direct evidence that the mutations in CYLD can cause two clinically distinct cancer syndromes.

China↗

PubMed2006

Differential expression of TGFbeta-stimulated clone 22 in normal prostate and prostate cancer.

The transforming growth factor-beta (TGFbeta) superfamily and its downstream effector genes are key regulators of epithelial homeostasis. Altered expression of these genes may be associated with malignant transformation of the prostate gland. The cDNA array analysis of differential expression of the TGFbeta superfamily and functionally related genes between patient-matched noncancerous prostate (NP) and prostate cancer (PC) bulk tissue specimens highlighted two genes, namely TGFbeta-stimulated clone-22 (TSC-22) and Id4. Verification of their mRNA expression by real-time PCR in patient-matched NP and PC bulk tissue, in laser-captured pure epithelial and cancer cells and in NP and PC cell lines confirmed TSC-22 underexpression, but not Id4 overexpression, in PC and in human PC cell lines. Immunohistochemical analysis showed that TSC-22 protein expression in NP is restricted to the basal cells and colocalizes with the basal cell marker cytokeratin 5. In contrast, all matched PC samples lack TSC-22 immunoreactivity. Likewise, PC cell lines do not show detectable TSC-22 protein expression as shown by immunoblotting. TSC-22 should be considered as a novel basal cell marker, potentially useful for studying lineage determination within the epithelial compartment of the prostate. Conversely, lack of TSC-22 seems to be a hallmark of malignant transformation of the prostate epithelium. Accordingly, TSC-22 immunohistochemistry may prove to be a diagnostic tool for discriminating benign lesions from malignant ones of the prostate. The suggested tumour suppressor function of TSC-22 warrants further investigation on its role in prostate carcinogenesis and on the TSC-22 pathway as a candidate therapeutic target in PC.

Aged↗

PubMedDate not supplied

Proteomics and regulomics: the yin and yang of functional genomics.

Protein analysis is a field of research with a long history. Recently, the development of a series of proteomics approaches, i.e., simultaneous analyses on all or a majority of proteins in a cell at a given state, has reinvigorated protein analyses. Mass Spectrometry also developed into one of the most versatile technical tools supporting or even enabling many proteomics-oriented approaches, providing a convenient link between experimental protein analysis and the corresponding amino acid sequences. Thus direct links to the genomic sequence can be established, which opens the door for a synergistic combination with genomic sequence analysis. This review focuses especially on aspects of genome-wide transcription control, regulomics in analogy to all the other -omics, and how a combination of MS-based proteomics with in silico regulomics analyses can produce synergistic effects in the quest to understand how cells function. This is illustrated on a real life example showing how the MS-analysis and in silico promoter analysis can extend the list of candidates for signaling pathways, here the MAP kinase pathway.

Energy Metabolism↗

PubMed2001

Genetic determinants of basal cell carcinoma risk.

Basal cell carcinomas are can be induced by ionizing radiation, in particular in patients with the rare autosomal dominant basal cell nevus syndrome (BCNS). These patients also are prone to medulloblastomas, and curative ionizing radiation therapy for the latter is followed soon by the development of sheets of basal cell carcinomas in the overlying skin. Positional cloning of the gene mutant is BCNS patients has identified the hedgehog signaling pathway as crucial to the development of all basal cell carcinomas and presumably to this susceptibility to post-ionizing radiation carcinogenesis. Thus this pathway is a candidate for susceptibility to second, post-therapy cancers in the broader population.

Animals↗

PubMed1997

Role for CD40-mediated activation of c-Rel and maintenance of c-myc RNA levels in mitigating anti-IgM-induced growth arrest.

CD40 crosslinking on B cells activates NF-kappaB and stress-activated protein kinase (SAPK) pathways. Since CD40 crosslinking rescues WEHI 231 B cells from anti-IgM-induced apoptosis, those pathways were likely candidates to be involved. Indeed, both signaling cascades predominated in anti-IgM-treated WEHI 231 cells, treated concurrently with anti-CD40 to rescue them from apoptosis. Crosslinking of CD40 activated the NF-kappaB proteins c-Rel and p50, but had no influence on their cytoplasmic steady state level. However, in contrast to-and even in the presence of-anti-IgM-mediated signals, engagement of CD40 resulted in a prolonged nuclear translocation of c-Rel, thereby allowing the formation of active NF-kappaB complexes. Consistent with this, the upstream regulatory element of the c-myc promoter, known to be regulated by NF-kappaB, was differently regulated after BCR ligation vs BCR plus CD40 crosslinking. The level of c-myc RNA was rapidly downregulated after BCR engagement, but persistent in the presence of CD40 signaling.

Animals↗

PubMed2002

Purification and characterization of recombinant Plasmodium falciparum adenylosuccinate synthetase expressed in Escherichia coli.

Most parasitic protozoa lack the de novo purine biosynthetic pathway and rely exclusively on the salvage pathway for their purine nucleotide requirements. Enzymes of the salvage pathway are, therefore, candidate drug targets. We have cloned the Plasmodium falciparum adenylosuccinate synthetase gene. In the parasite, adenylosuccinate synthetase is involved in the synthesis of AMP from IMP formed during the salvage of the purine base, hypoxanthine. The gene was shown to code for a functionally active protein by functional complementation in a purA mutant strain of Escherichia coli, H1238. This paper reports the conditions for hyperexpression of the recombinant protein in E. coli BL21(DE3) and purification of the protein to homogeneity. The enzyme was found to require the presence of dithiothreitol during the entire course of the purification for activity. Glycerol and EDTA were found to stabilize enzyme activity during storage. The specific activity of the purified protein was 1143.6 +/- 36.8 mUnits/mg. The K(M)s for the three substrates, GTP, IMP, and aspartate, were found to be 4.8 microM, 22.8 microM, and 1.4 mM, respectively. The enzyme was a dimer on gel filtration in buffers of low ionic strength but equilibrated between a monomer and a dimer in buffers of increased ionic strength.

Adenylosuccinate Synthase↗

PubMed1995

Evidence against involvement of recoverin in autosomal recessive retinitis pigmentosa in 42 Spanish families.

Autosomal recessive retinitis pigmentosa (ARRP) is a degenerative disease of photoreceptors in which defects in the genes encoding rhodopsin, the beta subunit of rod phosphodiesterase (PDEB) and, recently, in the gene for rod cGMP-gated channel, have been reported. However, detailed genetic involvement has not been ascertained in the great majority of cases. Recoverin, another member of the light transduction pathway, is a candidate gene for ARRP. We report the first analyses of the involvement of the recoverin gene (RCV1) in 42 Spanish ARRP families. Linkage and homozygosity studies with an intragenic polymorphism and the close markers D17S945 and D17S786 ruled out RCV1 as the cause of ARRP in 38 pedigrees. In the four remaining families, single strand conformation polymorphism analysis of the recoverin-coding region detected no mutations in the parents or in the affected members. These results strongly suggest that mutations in the RCV1 gene are not responsible for ARRP in these families.

Base Sequence↗

PubMed2005

Mitochondrial ceramide and the induction of apoptosis.

In most cell types, a key event in apoptosis is the release of proapoptotic intermembrane space proteins from mitochondria to the cytoplasm. In general, it is the release of these intermembrane space proteins that is responsible for the activation of caspases and DNases that are responsible for the execution of apoptosis. The mechanism for the increased permeability of the mitochondrial outer membrane during the induction phase of apoptosis is currently unknown and highly debated. This review will focus on one such proposed mechanism, namely, the formation of ceramide channels in the mitochondrial outer membrane. Ceramides are known to play a major regulatory role in apoptosis by inducing the release of proapoptotic proteins from the mitochondria. As mitochondria are known to contain the enzymes responsible for the synthesis and hydrolysis of ceramide, there exists a mechanism for regulating the level of ceramide in mitochondria. In addition, mitochondrial ceramide levels have been shown to be elevated prior to the induction phase of apoptosis. Ceramide has been shown to form large protein permeable channels in planar phospholipid and mitochondrial outer membranes. Thus, ceramide channels are good candidates for the pathway with which proapoptotic proteins are released from mitochondria during the induction phase of apoptosis.

Animals↗