Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrations of apoptosis are implicated in many diseases, including cancer, autoimmune disease, cardiovascular disease and neurodegeneration. The cell's apoptotic machinery is, therefore, an important potential target for the development of new therapies. Our laboratory has used a strategy called technical knockout (TKO) to identify novel genes involved in apoptosis. TKO is based on random inactivation of gene expression with antisense cDNA libraries, followed by selection of those cells that survive in the continuous presence of an apoptotic stimulus. Using this approach, we have isolated five novel genes, including a serine/threonine kinase, a nucleotide-binding protein and a homologue of the p220 translation initiation factor. Expression of one of these genes (DAP kinase) is lost in some cancers, and this loss appears to increase the metastatic potential of some tumours.
Mol Med Today 1998 Jun
PMID:Death-associated proteins: from gene identification to the analysis of their apoptotic and tumour suppressive functions. 967 46

Using a rat model of isocaloric protein restriction (8 v 20% protein diet), the study tested the hypothesis that growth retardation in utero, induced by maternal protein malnutrition, influences cardiac carnitine palmitoyltransferase (CPT) activity and regulation by malonyl-CoA in the newborn period, as well as in the offspring's adult life. The susceptibility of cardiac CPT to inhibition by malonyl-CoA was greater in adulthood than in hearts of 4-day-old neonatal rats, consistent with decreased expression of the L-CPT I isoform and increased expression of the M-CPT I isoform in adulthood. Maternal protein restriction during pregnancy resulted in reduced foetal growth and significantly (P < 0.05) lower rates of cardiac glucose utilization in vivo in the adult offspring, suggesting a switch to the use of substrates other than glucose. Maternal protein restriction did not affect CPT activity in hearts of 4-day-old neonatal offspring and, furthermore, the relative sensitivity of CPT activity to malonyl-CoA inhibition was unchanged by maternal protein restriction. It is therefore unlikely that maternal protein malnutrition has any major impact on cardiac mitochondrial fatty acid oxidation in the offspring during early postnatal development through altered regulatory characteristics of CPT. Transfer of rats previously maintained on 8% protein diet to 20% protein diet at weaning did not influence age-dependent changes in cardiac CPT activity or increase the susceptibility of cardiac CPT to inhibition by malonyl-CoA. Cardiac CPT activities and the susceptibility of cardiac CPT activities to malonyl-CoA inhibition in adulthood did not differ significantly between rats maintained on 8 or 20% protein throughout. Palmitate oxidation was suppressed to a similar extent by glucose in cardiac myocytes from adult rats maintained on 20% protein diet or 8% protein diet throughout and from rats transferred from 8 to 20% protein diet at weaning. The results exclude cardiac CPT activity as a direct target for the metabolic programming of cardiac function and cardiovascular disease associated with early growth retardation.
J Mol Cell Cardiol 1998 Jul
PMID:Impact of protein restriction on the regulation of cardiac carnitine palmitoyltransferase by malonyl-CoA. 971 Aug 6

Linkage and segregation analysis have shown that circulating angiotensin-I converting enzyme (ACE) levels are influenced by a major quantitative trait locus that maps within or close to the ACE gene. The D variant of a 287 bp insertion/deletion (I/D) polymorphism in intron 16 of the gene is associated with high ACE levels and may also be related to increased risk of cardiovascular disease. Multiple variants that are in linkage disequilibrium with the I/D polymorphism have been described, but it is unknown if any of these are directly implicated, alone or in combination with as yet undiscovered variants, in the determination of ACE levels. An analysis of 10 polymorphisms spanning 26 kb of the ACE gene revealed a limited number of haplotypes in Caucasian British families due to strong linkage disequilibrium operating over this small chromosomal region. A haplotype tree (cladogram) was constructed with three main branches (clades A-C) which account for 90% of the observed haplotypes. Clade C is most likely derived from clades A and B following an ancestral recombination event. This evolutionary information was then used to direct a series of nested, measured haplotype analyses that excluded upstream sequences, including the ACE promoter, from harbouring the major ACE-linked variant that explains 36% of the total trait variability. Residual familial correlations were highly significant, suggesting the influence of additional unlinked genes. Our results demonstrate that a combined cladistic/measured haplotype analysis of polymorphisms within a gene provides a powerful means to localize variants that directly influence a quantitative trait.
Hum Mol Genet 1998 Oct
PMID:Measured haplotype analysis of the angiotensin-I converting enzyme gene. 973 76

A common missense mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been shown to be a risk factor for premature cardiovascular disease and neural tube defect. Deficient activity of MTHFR has also been implicated in the pathogenesis of psychiatric conditions such as schizophrenia and affective disorders. Arinami et al found an increased frequency of homozygosity for the mutated type (T677) of the MTHFR gene in schizophrenia and depression. We tried to replicate this finding in a sample of 343 patients with schizophrenia, 143 with bipolar disorder, 71 with unipolar depression, and 258 controls; however, there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls. Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.
Mol Psychiatry 1998 Sep
PMID:C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. 1020 43

There is mounting evidence to suggest that Chlamydia pneumoniae might play a role in atherosclerosis. Serological studies and detection of the microorganism in atheromatous lesions were the first indications of an association between C. pneumoniae and the disease. Studies suggest that anti-chlamydial chemotherapy has a favorable effect on cardiovascular disease in humans. Moreover, infection of animals with C. pneumoniae induces inflammatory changes in the aorta that are suggestive of atherosclerosis and accelerates the progression of existing atherosclerotic lesions. If the pathogenic role of C. pneumoniae in atherosclerosis is defined more conclusively by future studies, the development of preventive or therapeutic measures against infection might provide an effective strategy to reduce the risk of atherosclerosis.
Mol Med Today 1998 Oct
PMID:Is infection with Chlamydia pneumoniae a causative agent in atherosclerosis? 979 30

Cigarette smoking is associated with impaired endothelium-dependent vasodilation and reduced nitric oxide (NO) in the exhaled air of smokers. To explore the mechanism for the impairment of NO-mediated vasodilation, we studied the effect of cigarette smoke extract (CSE) on NO synthase (eNOS) activity and content in pulmonary artery endothelial cells (PAEC). Incubation of PAEC with CSE resulted in a time- and dose-dependent decrease in eNOS activity. The inhibitory effect of CSE on eNOS activity was not reversible. Both gas-phase and particulate-phase extracts of CSE contributed to the inhibition of eNOS activity. The protein kinase c (PKC) inhibitors staurosporine and chelerythrine did not affect the CSE-induced inhibition of eNOS activity. Catalase, superoxide dismutase (SOD), vitamin C, vitamin E, glutathione, and dithiothreitol (DTT) also did not prevent the CSE-induced inhibition of eNOS activity, and incubation of PAEC with 3 mM nicotine did not change the activity of eNOS. Treatment of PAEC with CSE also caused a nonreversible, time-dependent decrease in eNOS protein content detected by Western blot analysis, and in eNOS messenger RNA (mRNA) detected by Northern blot analysis. Treatment of PAEC with CSE had no effect on cell protein or glutathione contents or on lactate dehydrogenase (LDH) release. These results indicate that exposure to CSE causes an irreversible inhibition of eNOS activity in PAEC, and suggest that the decreased activity is secondary to reduced eNOS protein mass and mRNA. The decrease in eNOS activity may contribute to the high risk of pulmonary and cardiovascular disease in cigarette smokers.
Am J Respir Cell Mol Biol 1998 Nov
PMID:Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. 980 47

The JCR:LA-cp rat is one of a number of strains that carry the mutant autosomal recessive cp gene. Animals, of all strains, that are homozygous, for the gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic. Heterozygotes or homozygous normal rats (+/+) are lean and metabolically normal. The JCR:LA-cp rat is unique in the development of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly correlated with the hyperinsulinemia, which develops as the animals mature from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the postprandial glucose and insulin responses through the use of alpha-glucosidase inhibitors. Any treatment that reduces plasma insulin levels is associated with a reduction in cardiovascular disease. In contrast, a reduction in plasma triglyceride concentrations, alone, has no effect on end-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, are, however, sensitive to cholesterol in the diet, unlike other strains that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperplastic and activated and migrate into the intimal space. Our findings suggest that susceptibility to cardiovascular disease requires hypermsulinemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. One of these may be a genetic abnormality of vascular smooth muscle cells. A similar situation may occur in humans.
Mol Cell Biochem 1998 Nov
PMID:Cardiovascular disease in the JCR:LA-cp rat. 982 17

Porphyromonas gingivalis, a gram-negative anaerobe, is a major etiological agent in the initiation and progression of severe forms of periodontal disease. An opportunistic pathogen, P. gingivalis can also exist in commensal harmony with the host, with disease episodes ensuing from a shift in the ecological balance within the complex periodontal microenvironment. Colonization of the subgingival region is facilitated by the ability to adhere to available substrates such as adsorbed salivary molecules, matrix proteins, epithelial cells, and bacteria that are already established as a biofilm on tooth and epithelial surfaces. Binding to all of these substrates may be mediated by various regions of P. gingivalis fimbrillin, the structural subunit of the major fimbriae. P. gingivalis is an asaccharolytic organism, with a requirement for hemin (as a source of iron) and peptides for growth. At least three hemagglutinins and five proteinases are produced to satisfy these requirements. The hemagglutinin and proteinase genes contain extensive regions of highly conserved sequences, with posttranslational processing of proteinase gene products contributing to the formation of multimeric surface protein-adhesin complexes. Many of the virulence properties of P. gingivalis appear to be consequent to its adaptations to obtain hemin and peptides. Thus, hemagglutinins participate in adherence interactions with host cells, while proteinases contribute to inactivation of the effector molecules of the immune response and to tissue destruction. In addition to direct assault on the periodontal tissues, P. gingivalis can modulate eucaryotic cell signal transduction pathways, directing its uptake by gingival epithelial cells. Within this privileged site, P. gingivalis can replicate and impinge upon components of the innate host defense. Although a variety of surface molecules stimulate production of cytokines and other participants in the immune response, P. gingivalis may also undertake a stealth role whereby pivotal immune mediators are selectively inactivated. In keeping with its strict metabolic requirements, regulation of gene expression in P. gingivalis can be controlled at the transcriptional level. Finally, although periodontal disease is localized to the tissues surrounding the tooth, evidence is accumulating that infection with P. gingivalis may predispose to more serious systemic conditions such as cardiovascular disease and to delivery of preterm infants.
Microbiol Mol Biol Rev 1998 Dec
PMID:Life below the gum line: pathogenic mechanisms of Porphyromonas gingivalis. 984 71

The incidence of certain ageing sequelae such as lung and cardiovascular disease and cataract are higher in smokers than in non-smokers. We recently proposed that certain components of mainstream cigarette smoke can react with plasma and extracellular matrix proteins to form covalent adducts with many of the properties of advanced glycation endproducts (AGE). AGEs have been implicated previously in the pathogenesis of the end-organ complications of diabetes and ageing, including cataract, atherosclerosis and renal insufficiency. In these circumstances, AGEs arise in vivo from the non-enzymatic reaction of reducing sugars with amino groups. Over time the initial Schiff base and Amadori products that form gradually undergo dehydration and rearrangement to produce reactive, carbonyl containing compounds with characteristic fluorescence and covalent crosslinking properties. Recent studies indicate that in smokers, tobacco-derived AGEs accumulate on plasma low density lipoprotein (LDL), structural proteins present within the vascular wall, and the lens proteins of the eye. These data point to a new and significant source of Maillard products in the human environment, significantly broaden the role of Maillard chemistry in pathological processes, and provide new insight into the pathogenesis of atherosclerosis and other diseases associated with tobacco usage.
Cell Mol Biol (Noisy-le-grand) 1998 Nov
PMID:Advanced glycation endproducts and cigarette smoking. 984 84

Pulmonary fibrosis begins with alveolitis, which progresses to destruction of lung tissue and excess collagen deposition. This process could be the result of DNA damage and a form of apoptosis. Therefore, we hypothesized that Fas ligand (FasL), which induces apoptosis in cells expressing Fas antigen (Fas), is associated with pulmonary fibrosis. We examined frozen lung tissues from seven patients with idiopathic pulmonary fibrosis (IPF), and bronchoalveolar lavage fluid (BALF) cells from 19 patients with IPF and from 17 patients with interstitial pneumonia associated with collagen vascular diseases (CVD-IP). We used five frozen lungs with normal lung parenchyma and BALF cells from 10 patients with solitary pulmonary nodule as controls. Reverse transcription-polymerase chain reaction (RT-PCR) showed that FasL messenger RNA (mRNA) was expressed in BALF cells from all patients with IPF and from 15 of 16 patients with CVD-IP. FasL mRNA was not detected in BALF cells except in one of 10 controls. RT in situ PCR detected FasL mRNA in inflammatory cells in BALF from patients with IPF. Immunohistochemistry detected FasL protein in infiltrating lymphocytes and granulocytes in all of seven frozen lung tissues of IPF, but in none of five control lung tissues. Additionally, the expression of Fas appeared to be upregulated in bronchiolar and alveolar epithelial cells in IPF compared with normal lung parenchyma by immunohistochemistry. We conclude that Fas and FasL were upregulated in fibrosing lung diseases and may associate with DNA damage or apoptosis of bronchiolar and alveolar epithelial cells in this disorder.
Am J Respir Cell Mol Biol 1999 Jan
PMID:The involvement of Fas-Fas ligand pathway in fibrosing lung diseases. 987 Sep 17


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