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PubMed2000

Senescence and immortalization of human cells.

Following a limited number of population doublings (PD), human diploid somatic cells enter the terminal proliferation arrest state of senescence. This is an intrinsic mechanism which involves p53- and pRB/p16INK4-mediated pathways. The most popular candidate for the counting mechanism which measures the age of a cell in PD is telomere shortening. Recent studies have shown that senescence can also be induced independently of a PD level by various factors; this premature senescence also appears to involve the activity of p53 and/or p16INK4. Immortalization of cells requires abrogation of p53 and pRB-mediated terminal proliferation arrest and/or activation of a telomere maintenance mechanism. The central role of telomeres in human cell senescence and immortalization has received much attention; however there is evidence that senescence can occur independently of telomere length and that genes that are not necessarily involved in telomere maintenance are involved in immortalization.

Animals↗

PubMed1998

Developmental and hormonal regulation of protein N-glycosylation in the mammary gland.

Glycosylation represents the most common conjugation of both membrane-bound and secreted proteins of animal cells. Among the different types of glycosylation, the N-linked attachment of sugars to the polypeptide backbone is by far the most abundant modification. The biosynthesis of the precursor carbohydrate unit of these proteins is initiated by a stepwise assembly of Glc3Man9GlcNAc2P-P-Dol in the dolichol cycle, its transfer en bloc to the nascent polypeptide in the rough endoplasmic reticulum (RER), followed by excision of the glucosyl residues by processing-specific enzymes, glucosidase I and II, also resident in the endoplasmic reticulum. Additional posttranslational modifications of the carbohydrate moiety in the RER, Golgi, and trans-Golgi network, differ for individual glycoproteins for the completion of final products as high mannose, complex or hybrid glycoproteins en route to their final destinations in the secretory pathway. The enzyme GlcNAc-1-P transferase (GPT) catalyzes the first and committed step, i.e., the transfer of GlcNAc-1-P from UDP-GlcNAc to Dol-P to form GlcNAc-P-P-Dol, in the assembly of the oligosaccharide precursor. Glucosidase I triggers the maturation phase by clipping the distal alpha 1,2-linked Glc residue on the incipient glycoprotein. The critical juxtaposition of the two enzymes in the multistep pathway makes them excellent candidates for the overall regulation of protein N-glycosylation. The highly elevated needs of glycosylation during lactation demand regulation of glycosylation in the gland over and above the levels in the quiescent, virgin and postlactating, regressed gland.

Animals↗

PubMed2003

Synthesis and immunogenic properties of phosphopeptides related to the human insulin receptor.

Two phosphoserine tetradecapeptides corresponding to sequences 987-1000 (peptide pSer994) and 1017-1030 (peptide pSer1023/1025) from the human insulin receptor involved in the regulation of its activity were successfully synthesized using Fmoc-based chemistry. Phosphorylation was performed by post-assembly phosphitylation followed by oxidation. The selective phosphorylation of Ser residues was achieved incorporating into the peptide chain the Ser (Trt) derivative and t-Bu blocking groups at sites other than those intended to be phosphorylated. The Trt group was selectively removed with dichloroacetic acid while under this condition t-Bu protecting groups remained unaltered. Following conjugation to keyhole limpet hemocyanin phosphopeptides were used as immunogens to generate sequence-specific phosphoserine antibodies. Peptide pSer994 induced antibodies in New Zealand white rabbits which discriminated between the phosphorylated and nonphosphorylated forms of the peptide, thus representing promising candidates to recognize signaling pathways associated to the regulation of the human insulin receptor.

Amino Acid Sequence↗

PubMed1994

Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by combined systemic degeneration of the dentatofugal and pallidofugal pathways. We investigated a candidate gene and found that DRPLA patients had an expanded CAG trinucleotide repeat in a gene on the short arm of chromosome 12. The repeat size varied from 7-23 in normal individuals. In patients one allele was expanded to between 49-75 repeats or occasionally even more. Expansion was usually associated with paternal transmission and only occasionally with maternal transmission. Repeat size showed a close correlation with age of onset of symptoms and disease severity. We conclude that DRPLA is the seventh genetic disorder known to be associated with expansion of an unstable trinucleotide repeat.

Alleles↗

PubMed2005

Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations.

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNgammaR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNgamma. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations ( approximately 1.4%) in 77 genes ( approximately 13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.

Anti-Bacterial Agents↗

PubMed2002

Hypoxia--a key regulatory factor in tumour growth.

Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

Animals↗

PubMed2003

Definition of polymorphisms in the gene encoding the interleukin-12 receptor B1 subunit: testing linkage disequilibrium with Type I diabetes susceptibility.

The cytokine interleukin (IL)-12 is bound by a heterodimeric receptor and mediates a range of immunological activities, in particular, favouring the development of uncommitted T cells to the Th1 phenotype. Genes encoding elements of the IL-12 pathway are therefore good candidates for mediating susceptibility or resistance to a range of immune disorders, including Type I diabetes. We made a systematic search for variants in the human gene encoding the low-affinity IL-12 receptor, IL12RB1. Four single-nucleotide polymorphisms and two microsatellite polymorphisms were defined. We also tested these IL12RB1 alleles for involvement in Type I diabetes susceptibility, testing 131 families. Although suggestive evidence for linkage to a susceptibility gene was found, none of the IL12RB1 variants we defined demonstrated preferential transmission in these families.

Diabetes Mellitus, Type 1↗

PubMed2002

In vitro differentiation of WB-F344 rat liver epithelial cells into the biliary lineage.

Differentiation of hepatic precursor cells in the biliary lineage has rarely been investigated, owing to the lack of convenient in vitro models. In this study, we used sodium butyrate and culture on Matrigel to promote differentiation of WB-F344 rat liver epithelial cells along the biliary phenotype. This differentiation was assessed by following the expression of phenotypic markers at the protein or mRNA level. Sodium butyrate induced cytokeratin 19 expression and gamma-glutamyltranspeptidase activity, together with a large increase in gamma-glutamyltranspeptidase mRNA IV, a transcript expressed at high levels in biliary cells. We also observed an increase in aquaporin-1 and beta4 integrin mRNAs, encoding two proteins expressed in adult biliary cells. Culture on Matrigel increased cytokeratin 19, gamma-glutamyltranspeptidase, and BDS7 expression in WB-F344 cells which still expressed aquaporin-1 and beta4 integrin. These results show that WB-F344 cells are able to differentiate in vitro along the biliary pathway, making them a candidate model for analyzing the molecular events associated with the hepatoblast-biliary cell transition.

Animals↗

PubMed2005

Antibody arrays in cancer research.

Antibody arrays have valuable applications in cancer research. Many different antibody array technologies have been developed, each with particular advantages, disadvantages, and optimal applications. The methods have been demonstrated on various sample types, such as serum, plasma, and other bodily fluids; cell culture supernatants; tissue culture lysates; and resected tumor specimens. The applications to cancer research have included profiling proteins to identify candidate biomarkers, characterizing signaling pathways, and the measurement of changes in modification or expression level of cancer-related proteins. Further innovations in the methods and experimental strategies are broadening the scope of the applications and the type of information that can be gathered. These alternate formats and uses of antibody arrays include arrays to measure whole cells, arrays to measure enzyme activities, reverse phase arrays, and bead-based arrays. This article reviews the various types of antibody array methods and their applications to cancer research.

Animals↗

PubMed2002

Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism.

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Werner Syndrome as an example of inflamm-aging: possible therapeutic opportunities for a progeroid syndrome?

Werner syndrome (WS) is a premature aging disorder that is widely used as a model for some aspects of the normal human aging process. Individuals with WS have several of the characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. In addition, WS is associated with high levels of inflammatory diseases such as atherosclerosis and type II diabetes. Recent data have indicated that fibroblasts derived from individuals with WS have activated a major molecular pathway involved in inflammation. This observation ties in with the presence of high plasma levels of inflammatory cytokines in individuals with WS. In this paper, the authors discuss the possibility that WS is an example of "inflamm-aging," in that many of the phenotypic manifestations may result from an increased inflammatory state. Moreover, drugs that specifically block this inflammation pathway may be possible candidates for therapeutic intervention in WS.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1990

Assessment of human vitamin C status.

Since no reliable functional markers of human vitamin C status have been demonstrated, determination of vitamin C levels in blood plasma and/or leukocytes remains the current choice for individual and population assessments. Newer analytical techniques, especially high-performance liquid chromatography, allow determination of reduced (ascorbic acid), oxidized (dehydroascorbic acid), or total amounts of vitamin C in biological specimens or foods. Plasma levels of vitamin C forms are easily determined but may not reflect tissue content as well as leukocyte levels. The vitamin C content of leukocyte cell types varies severalfold and, unlike plasma, leukocytes may contain an appreciable fraction of dehydroascorbic acid. The effects of sex, age, cigarette smoking, drugs, and physiological factors on vitamin C levels are better known for plasma than leukocytes. To realize the potential of leukocytes as measures of vitamin C status, continued work is needed in standardizing the methodology and interpretive guidelines and simplifying the technique for blood processing. The search for specific functional markers of vitamin C deficiency should continue. Candidate markers may involve pathways of carnitine or collagen metabolism, immunocompetence, or antioxidant defense.

Ascorbic Acid↗

PubMed2001

Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies.

We examined the immunoreactivity of ubiquitin-binding protein p62 and its association with ubiquitin (Ub), alpha-synuclein, and paired helical filament (PHF)-tau in the affected brain areas of human tauopathies and synucleinopathies. Ubiquitin-binding protein p62 is a widely expressed protein that can bind to Ub noncovalently and is involved in several signalling pathways, making p62 a candidate regulator of Ub-mediated proteolysis. We show that p62 immunoreactivity co-localizes with neuronal and glial Ub-containing inclusions in Alzheimer's disease, Pick's disease, dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. This is the first demonstration of a common protein component, apart from Ub, that is present in both PHF-tau and alpha-synuclein inclusions. In both tauo- and synucleinopathies, the staining patterns for p62 and Ub were markedly similar, suggesting that a common mechanism which requires interaction of p62 and Ub contributes to the formation of PHF-tau and alpha-synuclein inclusions.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Expression of insulin pathway genes during the period of caste determination in the honey bee, Apis mellifera.

Female honeybees have two castes, queens and workers. Developmental fate is determined by larval diet. Coding sequences made available through the Honey Bee Genome Sequencing Consortium allow for a pathway-based approach to understanding caste determination. We examined the expression of several genes of the insulin signalling pathway, which is central to regulation of growth based on nutrition. We found one insulin-like peptide expressed at very high levels in queen but not worker larvae. Also, the gene for an insulin receptor was expressed at higher levels in queen larvae during the 2nd larval instar. These results demonstrate that the insulin pathway is a compelling candidate for pursing the relationship between diet and downstream signals involved in caste determination and differentiation.

Animals↗

PubMed1996

Long-term depression in rat cerebellum requires both NO synthase and NO-sensitive guanylyl cyclase.

Long-term depression (LTD) of synaptic transmission between parallel fibres and Purkinje cells is a well-known example of synaptic plasticity taking place in the cerebellum. Nitric oxide (NO) has been implicated in synaptic plasticity in other brain areas, but its function in cerebellar LTD is controversial. Even when an involvement is suggested, the NO signal transduction pathway is unclear. One candidate is the cyclic GMP-synthesizing enzyme, soluble guanylyl cyclase, whose activity in the brain and elsewhere is powerfully stimulated by NO. By recording intracellularly from Purkinje cells in cerebellar slices, we demonstrate that blockade of NO synthase completely inhibits LTD induced by pairing parallel fibre stimulation with postsynaptic Ca2+ spike firing. LTD was also blocked by intracellular application of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a recently identified potent and selective inhibitor of soluble guanylyl cyclase. These findings indicate that soluble guanylyl cyclase is required for cerebellar LTD and suggest that this enzyme, located within Purkinje cells, transduces the NO signal in this form of synaptic plasticity.

Animals↗

PubMed2006

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

Adult↗

PubMed2004

The genomic sequence of the accidental pathogen Legionella pneumophila.

We present the genomic sequence of Legionella pneumophila, the bacterial agent of Legionnaires' disease, a potentially fatal pneumonia acquired from aerosolized contaminated fresh water. The genome includes a 45-kilobase pair element that can exist in chromosomal and episomal forms, selective expansions of important gene families, genes for unexpected metabolic pathways, and previously unknown candidate virulence determinants. We highlight the genes that may account for Legionella's ability to survive in protozoa, mammalian macrophages, and inhospitable environmental niches and that may define new therapeutic targets.

DNA, Bacterial↗

PubMed2006

Identification of an abscisic acid gene cluster in the grey mold Botrytis cinerea.

Like several other phytopathogenic fungi, the ascomycete Botrytis cinerea is known to produce the plant hormone abscisic acid (ABA) in axenic culture. Recently, bcaba1, the first fungal gene involved in ABA biosynthesis, was identified. Neighborhood analysis of bcaba1 revealed three further candidate genes of this pathway: a putative P450 monooxygenase-encoding gene (bcaba2), an open reading frame without significant similarities (bcaba3), and a gene probably coding for a short-chain dehydrogenase/reductase (bcaba4). Targeted inactivation of the genes proved the involvement of BcABA2 and BcABA3 in ABA biosynthesis and suggested a contribution of BcABA4. The close linkage of at least three ABA biosynthetic genes is strong evidence for the presence of an abscisic acid gene cluster in B. cinerea.

Abscisic Acid↗