Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Gapped and ungapped sequence alignment were tested as possible methods to classify proteins into the functional classes defined by the International Enzyme Commission (EC). We exhaustively tested all 15,208 proteins labeled with any EC class in a recent release of the SwissProt database, evaluating all 1,327 relevant EC classes. We effectively tested all possible similarity thresholds that could be used for this assignment through the use of the ROC statistic. Approximately 60% of Enzyme Commission classes containing two or more proteins could not be perfectly discriminated by sequence similarity at any threshold. An analysis of the errors indicates that false positive matches dominate, and that various error mechanisms can be identified, including the multidomain nature of many proteins and polyproteins, convergent evolution, variation in enzyme specificity, and other factors. Many of the putatively false positives are in fact biologically relevant. This work strongly suggests that functional assignment of enzymes should attempt to delimit functionally significant subregions, or domains, before matching to EC classes.
Proc Int Conf Intell Syst Mol Biol 1997
PMID:Predicting enzyme function from sequence: a systematic appraisal. 932 50

We have identified two highly conserved RING finger proteins, ROC1 and ROC2, that are homologous to APC11, a subunit of the anaphase-promoting complex. ROC1 and ROC2 commonly interact with all cullins while APC11 specifically interacts with APC2, a cullin-related APC subunit. YeastROC1 encodes an essential gene whose reduced expression resulted in multiple, elongated buds and accumulation of Sic1p and Cln2p. ROC1 and APC11 immunocomplexes can catalyze isopeptide ligations to form polyubiquitin chains in an E1- and E2-dependent manner. ROC1 mutations completely abolished their ligase activity without noticeable changes in associated proteins. Ubiquitination of phosphorylated I kappa B alpha can be catalyzed by the ROC1 immunocomplex in vitro. Hence, combinations of ROC/APC11 and cullin proteins proteins potentially constitute a wide variety of ubiquitin ligases.
Mol Cell 1999 Apr
PMID:ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. 1023 Apr 7

Members of the cullin and RING finger ROC protein families form heterodimeric complexes to constitute a potentially large number of distinct E3 ubiquitin ligases. We report here that the highly conserved C-terminal sequence in CUL1 is dually required, both for nuclear localization and for modification by NEDD8. Disruption of ROC1 binding impaired nuclear accumulation of CUL1 and decreased NEDD8 modification in vivo but had no effect on NEDD8 modification of CUL1 in vitro, suggesting that ROC1 promotes CUL1 nuclear accumulation to facilitate its NEDD8 modification. Disruption of NEDD8 binding had no effect on ROC1 binding, nor did it affect nuclear localization of CUL1, suggesting that nuclear localization and NEDD8 modification of CUL1 are two separable steps, with nuclear import preceding and required for NEDD8 modification. Disrupting NEDD8 modification diminishes the IkappaBalpha ubiquitin ligase activity of CUL1. These results identify a pathway for regulation of CUL1 activity-ROC1 and the CUL1 C-terminal sequence collaboratively mediate nuclear accumulation and NEDD8 modification, facilitating assembly of active CUL1 ubiquitin ligase. This pathway may be commonly utilized for the assembly of other cullin ligases.
Mol Cell Biol 2000 Nov
PMID:The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1. 1102 88

HIV-derived vectors are of potential clinical relevance due to their ability to transduce nondividing cells in vitro and in vivo. However, the generation of cell lines stably and reproducibly expressing high amounts of defined subviral particles, capable of packaging and transducing HIV-derived vectors, has been hampered by the cytotoxicity of some of the required gene products, in particular of the HIV-1 protease. The successful use of regulatable gene expression systems to overcome this problem requires that the remaining basally expressed gene product activity is below the threshold for cytotoxicity. To try to achieve this, we have consecutively introduced appropriate plasmids, encoding HIV rev and HIV gag/pol gene products, each under the control of separate ecdysone-inducible promoters, into human 293 cells. Using a protocol in which a specific HIV protease inhibitor, Saquinavir, was continuously present in the culture medium during selection, we could generate stable cell lines inducibly expressing high amounts of subviral particles. A cell line, termed 293-Rev/Gag/Pol(i), which has been characterized in more detail, inducibly releases, within 48 h postinduction, high amounts of HIV Gag/Pol particles (about 10 microg CA/ml). These HIV Gag/Pol particles can package and transduce third-generation HIV vectors to high titers. Thus, in addition to other applications, the 293-Rev/Gag/Pol(i) cell line represents a "founder" packaging cell line which, depending on the requirement, can be further modified to include specific transgene-encoding vector and targeting glycoprotein genes.
Mol Ther 2001 Apr
PMID:Generation of a flexible cell line with regulatable, high-level expression of HIV Gag/Pol particles capable of packaging HIV-derived vectors. 1131 23

The mechanisms by which bradykinin (BK) increases glucagon release were investigated. BK (0.1-10 microM) increased [Ca(2+)](i) and glucagon release in clonal alpha-cells In-R1-G9. BK-induced glucagon release was lower in the absence than in the presence of extracellular Ca(2+), but it still increased glucagon release while [Ca(2+)](i) was stringently deprived. Depletion of intracellular Ca(2+) store with thapsigargin abolished both the BK-induced Ca(2+) peak and sustained plateau. Microinjection of heparin abolished BK-induced Ca(2+) release. Pertussis toxin (PTX) did not block BK-induced [Ca(2+)](i) increase or glucagon release. U-73122 (8 microM), a phospholipase C (PLC) inhibitor, abolished BK-induced increases in [Ca(2+)](i), but only reduced BK-induced glucagon release by 40%. A phospholipase D (PLD) inhibitor zLYCK reduced BK-induced glucagon release by 60%. The combination of U-73122 and zLYCK abolished BK-induced glucagon release. Both SK&F 96365, a receptor-operated Ca(2+) channel (ROC) blocker and nimodipine, an L-type Ca(2+) channel blocker, reduced BK-induced [Ca(2+)](i) increase and glucagon release. These findings suggest that BK increase glucagon release through a PTX-insensitive G protein and both Ca(2+)-dependent and -independent pathways. The Ca(2+)-dependent pathway is attributable to PLC activation. PLC catalyzes IP(3) formation, inducing Ca(2+) release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx via both ROCs and L-type channels. PLD activation may be involved in Ca(2+)-dependent and/or -independent pathway.
Mol Cell Endocrinol 2002 Jun 28
PMID:Mechanisms of bradykinin-induced glucagon release in clonal alpha-cells In-R1-G9: involvement of Ca(2+)-dependent and -independent pathways. 1208 64

Myocardial viability can be defined as functional improvement of dysfunctional myocardium after revascularization. The purpose of this study was to define the optimal criteria for definition of regional functional improvement after coronary artery bypass graft (CABG) surgery on quantitative gated single-photon emission tomography (SPET). Thirty-two patients (26 men, 6 women; age 56 +/- 13 years) with coronary artery disease (three-vessel disease, 17; two-vessel disease, 15; previous history of myocardial infarction, 9) and severe left ventricular dysfunction (LVEF < or = 35%) underwent CABG. Rest thallium-201/dipyridamole stress technetium-99m methoxyisobutylisonitrile gated myocardial SPET was performed before and 3 months after CABG. Global LV functional improvement was defined as either an improvement in LVEF of 10% ( n = 15) or an improvement in LVEF of 5% combined with a decrease in end-systolic volume of 10 ml ( n = 2) after CABG on quantitative gated SPET. Postoperative regional wall thickening improvement (DeltaRWT), regional wall motion improvement (DeltaRWM) and regional resting (DeltaRP) and stress perfusion improvement (DeltaRstrP) were used to determine global functional improvement by ROC curve analysis, and the optimal criteria for definition of viable regional dysfunctional myocardium were defined on the ROC curves. Correlations were verified by determining the number of improved myocardial regions and LVEF improvement. LVEF was improved from 25% +/- 6% to 34% +/- 11% after CABG. A total of 229 segments were dysfunctional (wall motion < or = 2 mm, thickening < or = 20%) before CABG. On ROC curve analysis using global functional improvement as an indicator of viability, the areas under the ROC curves (AUCs) of DeltaRWT and DeltaRWM were 0.717 and 0.620, respectively. The AUC of DeltaRWT was significantly larger than that of DeltaRWM ( P = 0.009) and the optimal cut-off value of DeltaRWT was 15%. The AUCs of DeltaRP and DeltaRstrP were not significant. The correlation coefficients between summed DeltaRWT and DeltaRWM and LVEF improvement were 0.591 and 0.472, respectively. The number of segments with a DeltaRWT of more than 15% correlated with LVEF improvement (rho = 0.533 by Spearman rank correlation). Regional wall thickening improvement showed the best correlation with global LV functional improvement after CABG. The most reliable regional criterion of myocardial viability was improvement in regional wall thickening by > or = 15% on quantitative gated SPET.
Eur J Nucl Med Mol Imaging 2002 Aug
PMID:Criteria for definition of regional functional improvement on quantitative post-stress gated myocardial SPET after bypass surgery in patients with ischaemic cardiomyopathy. 1217 23

Cullin proteins assemble a large number of RING E3 ubiquitin ligases and regulate various physiological processes. Covalent modification of cullins by the ubiquitin-like protein NEDD8 activates cullin ligases through an as yet undefined mechanism. We show here that p120(CAND1) selectively binds to unneddylated CUL1 and is dissociated by CUL1 neddylation. CAND1 formed a ternary complex with CUL1 and ROC1. CAND1 dissociated SKP1 from CUL1 and inhibited SCF ligase activity in vitro. Suppression of CAND1 in vivo increased the level of the CUL1-SKP1 complex. We suggest that by restricting SKP1-CUL1 interaction, CAND1 regulated the assembly of productive SCF ubiquitin ligases, allowing a common CUL1-ROC core to be utilized by a large number of SKP1-F box-substrate subcomplexes.
Mol Cell 2002 Dec
PMID:NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases. 1250 25

The carbon-14 urea breath test (UBT) is a reliable and non-invasive technique for the diagnosis of Helicobacter pylori (HP) infection. In this study we evaluated the diagnostic performance of a new, practical and low-dose (14)C-UBT system for the diagnosis of HP and compared the results with those obtained using the standard method. Seventy-five patients (56 female, 19 male) with dyspepsia underwent (14)C-UBT and endoscopy with antral biopsies for histological analysis. The rapid urease test (CLO test) was applied to 50 of these patients. After a 6-h fasting period, a 37-kBq (14)C-urea capsule was swallowed for UBT. Breath samples were collected and counted using two different methods, the Heliprobe method and the standard method. In the Heliprobe method, patients exhaled into a special dry cartridge system (Heliprobe BreathCard) at 10 min. The activities of the cartridges were counted using a designated small GM counter system (Heliprobe analyser). Results were expressed both as counts per minute (HCPM) and as grade (0, not infected; 1, equivocal; 2, infected) according to the counts. In the standard method, breath samples were collected by trapping in a liquid CO(2) absorber. Radioactivity was counted as disintegrations per minute (SDPM) using a liquid scintillation counter after addition of a liquid scintillation cocktail. Histological examination was used as a gold standard. Two patients were excluded from the study because of inadequate biopsy sampling. Forty-eight patients (65%) were found to be HP positive on histology. The Heliprobe method correctly classified 48 of 48 HP-positive patients and 19 of 25 HP-negative patients (sensitivity 100%, specificity 76%, PPV 88%, NPV 100%, accuracy 91%). The standard method correctly classified 48 of 48 HP-positive patients and 20 of 25 HP-negative patients (sensitivity 100%, specificity 80%, PPV 90%, NPV 100%, accuracy 93%). On the other hand, the CLO test identified 26 of 32 HP-positive and 12 of 16 HP-negative patients (sensitivity 81%, specificity 75%, PPV 86%, NPV 66%, accuracy 79%). With the Heliprobe method, all of the positive results were grade 2, and all of the negative results were grade 0. No patients were defined as having grade 1 results. Counts allowed clear discrimination of HP-positive and -negative patients with both methods, the difference being statistically significant in each case ( P<0.001). A significant correlation was found between HCPM and SDPM ( r 0.863, P<0.001). According to the ROC analysis, the area under the curve was nearly the same with HCPM (AUC, 0.888; 95% CI, 0.785-0.992) and SDPM (AUC, 0.898; 95% CI, 0.802-0.994). In conclusion, the new (14)C-UBT system is a highly accurate method for the diagnosis of HP infection. It is rapid and practical, and therefore suitable for clinical and office practice.
Eur J Nucl Med Mol Imaging 2003 Nov
PMID:A new, practical, low-dose 14C-urea breath test for the diagnosis of Helicobacter pylori infection: clinical validation and comparison with the standard method. 1457 83

Patients diagnosed with mild cognitive impairment (MCI) have a higher risk of developing Alzheimer's disease (AD). However, not all such patients develop this kind of dementia. The purpose of this prospective study was to assess whether regional cerebral blood flow (rCBF) patterns measured with technetium-99m ethyl cysteinate dimer single-photon emission tomography ((99m)Tc-ECD SPET) in patients suffering from MCI are useful in predicting progression to AD. The study group comprised 42 patients who fulfilled MCI criteria according to the International Psychogeriatric Association and the Alzheimer's Disease Cooperative Study. rCBF was calculated in 16 regions of interest (ROIs). All patients were clinically assessed for 1-3 years. Twenty-one developed AD (group I) while the initial diagnosis of MCI was retained in the other 21 (group II). ROC curves were designed, and sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were determined for each ROI. Compared with group II (MCI), group I (AD) showed a significant reduction of relative blood flow (RBF), ranging from 7% to 10%, in the following areas: right and left prefrontal, right and left frontal, right and left parietal, right and left temporal, right and left frontoparietotemporal and left posterior lateral temporal. Left prefrontal, left frontal and left parietal areas showed sensitivities and specificities higher than 75% and areas below the ROC curve close to 80%. This study shows that RBF patterns in the right and left prefrontal, right and left frontal and left parietal areas are sensitive early markers of progression towards AD. Reduction of rCBF in the medial temporal and anterior lateral temporal cortex has no value as a predictor since it also occurs in patients with MCI who remain stable.
Eur J Nucl Med Mol Imaging 2003 Nov
PMID:Regional cerebral blood flow assessed with 99mTc-ECD SPET as a marker of progression of mild cognitive impairment to Alzheimer's disease. 1457 86

Candidate gene polymorphisms related to inflammation, thrombosis and lipid metabolism have been implicated in the development of ischemic stroke. Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years to prospectively determine whether candidate gene polymorphisms contribute to stroke risk. After adjustment for multiple comparisons and age, smoking, body mass index, hypertension, hyperlipidemia and diabetes, two related to inflammation [a val640leu polymorphism in the P-selectin gene (OR=1.63, 95% CI 1.22-2.17, P=0.001) and a C582T polymorphism in the interleukin-4 gene (OR=1.40, 95% CI 1.13-1.73, P=0.003)] were found to be independent predictors of thrombo-embolic stroke. In bootstrap replications, the inclusion of genetic information from these two polymorphisms improved prediction models for stroke based upon traditional risk factors alone (ROC 0.67 versus 0.64). Two polymorphisms related to thrombosis (an arg353gln polymorphism in the factor VII gene and a T11053G polymorphism in the plasminogen activator inhibitor type-1 gene) and one related to lipid metabolism [a C(-482)T polymorphism in the apolipoprotein CIII gene] achieved nominal significance, but were not found to be independent predictors after multiple comparison adjustment. Two inflammatory candidate gene polymorphisms were identified which were independently associated with incident stroke. These population-based data demonstrate the ability of prospective, epidemiological studies to test candidate gene associations for athero-thrombotic disease.
Hum Mol Genet 2004 Feb 15
PMID:Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis. 1468 4


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