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)

We examined 24 human bladder cancer tissues for possible mutations in the entire coding region of the human DNA polymerase beta gene using polymerase chain reaction analysis, single-strand conformational polymorphism analysis of RNA, and sequence analysis. DNA polymerase beta gene mutations were observed in four of the 24 cases (16.7%) and included three missense point mutations and a single base insertion. The single base insertion was also observed in our previous study of human prostate cancer, suggesting that this region may be a hot spot for mutation of the DNA polymerase beta gene. No clinical or pathological association was found among the four cases that contained the mutation. Three of the four cases with DNA polymerase beta gene mutation had mutations of the p16 or RB genes or loss of heterozygosity of the p53 and APC gene loci. The results of the study presented here suggest that DNA polymerase beta gene mutations, in combination with mutations of tumor suppressor genes, may be involved in certain cases of human bladder cancer.
Mol Carcinog 1996 Jan
PMID:DNA polymerase beta gene mutations in human bladder cancer. 856 64

The aim of our study was to determine the prevalence of the factor V mutation (position 1691 G-->A) in patients with angiographically diagnosed coronary artery disease and myocardial infarction and, as a control, in blood donors. This mutation has already been proved to be the main genetic risk factor for venous thrombosis. In order to detect this mutation in exon 10 of the factor V gene we established a microtiter plate based hybridization assay for the specific detection of wild-type and mutant sequences in factor V gene segments, obtained after amplification by polymerase chain reaction. This test enables us to screen a large number of samples. The mutation was detected in 29 of 317 coronary artery disease (CAD) patients (9.1%) and 18 of 190 blood donors (9.5%) investigated. The mean activated protein C resistance ratios were 3.18 and 3.11, with nearly identical distribution. No increased prevalence of the factor V mutation was found in the CAD group. In 10 of 29 CAD patients (35%) with the factor V 1691 G-->A mutation and in 124 of 288 CAD patients without the mutation (43%) there was a history of myocardial infarction. From our data we conclude that there is no increased risk of developing coronary atheroma or consecutive myocardial infarction resulting from the factor V mutation with protein C resistance.
J Mol Med (Berl) 1995 Oct
PMID:Evidence against heterozygous coagulation factor V 1691 G-->A mutation with resistance to activated protein C being a risk factor for coronary artery disease and myocardial infarction. 858 14

Measurements of the apparent affinity constant for thrombomodulin (TM) binding to human alpha-thrombin as a function of both NA+ and temperature at constant ionic strength (0.15 M) showed that TM affinity increases in the presence of Na+ and vice versa. Moreover, this experimental strategy allowed us to accurately split the free energy of sodium binding into its entropic and enthalpic components for both the TM-free and TM-bound enzyme. Namely, at 25 degrees C, the value of delta G of sodium binding was found equal to -2.4 kcal/mol in the absence of TM and -3.6 kcal/mol for the thrombin-TM complex. The enthalpic contribution to the free energy of sodium binding is equal to -27 kcal/mol and -21 kcal/mol in the TM-free and TM-bound thrombin forms, respectively. Finally, the entropy change for sodium binding was also affected by TM, being equal to -83 cal/(mol deg) and -58 cal/(mol deg) in TM-free and TM-bound thrombin species, respectively. Moreover, the thermodynamic parameters for TM binding to Na+-free thrombin species were solved. TM binding is characterized by an enthalpy and entropy change equal to -10 kcal/mol and 2 cal/(mol deg), respectively, for Na+-free thrombin. It is well known that Na+ binding to thrombin causes conformational transitions and functional activation of the enzyme molecule. The finding that binding of thrombomodulin enhances thrombin affinity for sodium and vice versa raises the question as to whether the change of Na+ ligation induced by TM binding could contribute to the change in thrombin specificity for the hydrolysis of Protein C. Therefore, the effect of sodium binding to thrombin on the hydrolysis of human Protein C was extensively investigated. At both 25 and 37 degrees C the value of kcat/Km for Protein C hydrolysis by thrombin in the absence of TM was found to be enhanced by Na+ over a concentration ranging from 0 to 150 mM. Application of thermodynamic principles demonstrated that the Na+-thrombomodulin linkage contributes, under physiological conditions of sodium activity and temperature, to reduce significantly the transition-state stabilization free energy for Protein C hydrolysis.
J Mol Biol 1996 Apr 26
PMID:Effect of sodium on the energetics of thrombin-thrombomodulin interaction and its relevance for protein C hydrolysis. 861 87

Colon carcinomas appear to arise from the cumulative effect of mutations to several genes (APC, DCC, p53, ras, hMLH1, and hMSH2). By using novel colonic epithelial cell lines derived from the Immorto mouse, named the YAMC (young adult mouse colon) cell line, and an Immorto-Min mouse hybrid, named the IMCE (Immorto-Min colonic epithelial) cell line, carrying the Apc min mutation, we investigated the effect of an activated v-Ha-ras gene on tumor progression. The YAMC and IMCE cell lines are normal colonic epithelial cell lines which are conditionally immortalized by virtue of expression of a temperature-sensitive simian virus 40 (SV40) large T antigen. Under conditions which permit expression of a functional SV40 large T antigen (33 degrees C plus gamma interferon), neither the YAMC nor the IMCE cell line grows in soft agar or is tumorigenic in nude mice. In vitro, when the SV40 large T antigen is inactivated (39 degrees C without gamma interferon), the cells stop proliferating and die. By infecting the YAMC and IMCE cell lines with a replication-defective psi2-v-Ha-ras virus, we derived cell lines which overexpress the v-Ha-ras gene (YAMC-Ras and IMCE-Ras). In contrast to the parental cell lines, under conditions in which the SV40 large T antigen is inactive, both the YAMC-Ras and IMCE-Ras cell lines continue to proliferate. Initally YAMC-Ras cells do not form tumors; however, tumors are visible after 90 days of incubation. IMCE-Ras cells form colonies in soft agar under both permissive and nonpermissive culture conditions. Furthermore, IMCE-Ras cells form tumors in nude mice within 3 weeks. The phenotype of the IMCE-Ras cell line thus clearly demonstrates that a defective Apc allele and an activated ras gene are sufficient to transform normal colonic epithelial cells and render them tumorigenic.
Mol Cell Biol 1996 Mar
PMID:Synergy between Apc min and an activated ras mutation is sufficient to induce colon carcinomas. 862 90

The Wnt-1 proto-oncogene induces the accumulation of beta-catenin and plakoglobin, two related proteins that associate with and functionally modulate the cadherin cell adhesion proteins. Here we have investigated the effects of Wnt-1 expression on the tumor suppressor protein APC, which also associates with catenins. Expression of Wnt-1 in two different cell lines greatly increased the stability of APC-catenin complexes. The steady-state levels of both catenins and APC were elevated by Wnt-1, and the half-lives of both beta-catenin and plakoglobin associated with APC were also markedly increased. The stabilization of catenins by Wnt-1 was primarily the result of a selective increase in the amount of uncomplexed, monomeric beta-catenin and plakoglobin, detected both by affinity precipitation and size-exclusion chromatography of cell extracts. Exogenous expression of beta-catenin was possible in cells already responding to Wnt-1 but not in the parental cells, suggesting that Wnt-1 inhibits an essential regulatory mechanism for beta-catenin turnover. APC has the capacity to oppose this Wnt-1 effect in experiments in which overexpression of the central region of APC significantly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1. Thus, the Wnt-1 signal transduction pathway leads to the accumulation of monomeric catenins and stabilization of catenin complex formation with both APC and cadherins.
Mol Cell Biol 1996 May
PMID:Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. 862 79

We investigated the effect of modifying the N- and/or C-termini of the snake toxin peptide 24-36 on its presentation to T cells. Acetylation at the N-terminus as well as amidation at the C-terminus enhanced the capacity of the peptide to activate T cells. Simultaneous modifications further increased the stimulating activity, the peptide becoming approximately 100-fold more potent than the unmodified peptide. Clearly, the introduced modifications increased the lifetime of the peptide free in solution, by decreasing its proteolytic degradation, during the T cell stimulation assays. Paradoxically, however, at similar concentrations of free peptides, the modified ones, especially those having an acetylated N-terminus, were much more active than the unmodified peptide, irrespective of the experimental conditions. These observations suggested that components other than protection from proteolytic degradation should be associated with the higher stimulating activities of the modified peptides. Accordingly, chasing experiments with APC revealed that acetylation at N-terminus caused a higher persistence of the peptides at APC surface. Together, our data indicate that (i) the T cell stimulating capacity of a peptide is associated with its lifespans in the free and MHC II bound states; and (ii) these lifespans can be greatly enhanced by introducing fine chemical modifications at N- and C-termini. These data may have some implications in designing more potent peptidic immunomodulators.
Mol Immunol 1995 Dec
PMID:Fine chemical modifications at N- and C-termini enhance peptide presentation to T cells by increasing the lifespan of both free and MHC-complexed peptides. 864 7

We evaluated the roles of plasma endothelin-1 and plasma thrombomodulin in the development of disseminated intravascular coagulation (DIC) in patients with sepsis. Plasma endothelin-1 was measured by radioimmunoassay (RIA). Plasma thrombomodulin and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay (ELISA), and serum protein C (protein C) was measured by the synthetic substrate method. Endotoxin was measured by the Endospecy test, a synthetic substrate method. A new perchloric acid method was used for the pretreatment of plasma. Blood levels of endothelin-1 and thrombomodulin were significantly higher in patients with DIC than in those without DIC (p < 0.0001). Endothelin-1 and thrombomodulin levels were positively correlated (r = 0.8645, p = 0.0001), as were endothelin-1 and TNF-alpha levels (r = 0.5441, p = 0.0002). Thrombomodulin and protein C levels were negatively correlated (r = -0.5627, p = 0.0001). Endotoxin was elevated above the normal level 14.3% (6/42) for these patients. TNF-alpha is involved in the production of endothelin-1 and thrombomodulin, which play a role in the pathogenesis of DIC and whose blood levels reflect its severity.
Res Commun Mol Pathol Pharmacol 1995 Nov
PMID:Blood levels of endothelin-1 and thrombomodulin in patients with disseminated intravascular coagulation and sepsis. 874 95

NtrC (nitrogen regulatory protein C) is a bacterial enhancer-binding protein that activates transcription by catalyzing isomerization of closed complexes between sigma54-holoenzyme and a promoter to open complexes. To catalyze this reaction, NtrC must be phosphorylated and form an appropriate oligomer so that it can hydrolyze ATP. NtrC can also repress transcription by sigma70-holoenzyme. In this paper we characterize "repressor" mutant forms of NtrC from Salmonella typhimurium, forms that have lost the ability to activate transcription by sigma54-holoenzyme (in vitro activity at least 1000-fold lower than wild-type) but retain the ability to repress transcription by sigma70-holoenzyme. The amino acid substitutions in NtrCrepressor proteins that were obtained by classical genetic techniques alter residues in the central domain of the protein, the domain directly responsible for transcriptional activation. Commensurate with this, phosphorylation and the autophosphatase activities of NtrCrepressor proteins, which are functions of the amino-terminal regulatory domain of NtrC, are normal. In addition, these proteins have essentially normal DNA-binding, which is a function of the C-terminal region of NtrC and bind cooperatively to enhancers. (The NtrC(G219K) protein has "improved" DNA-binding, which is discussed.) We previously presented evidence that several NtrCrepressor proteins have impaired ATPase activity. We now show that two other repressor proteins, NtrC(A216V) and NtrC(A220T), have as much ATPase activity as wild-type NtrC when they are phosphorylated and bound to an enhancer and that they have considerably more activity than an unphosphorylated NtrC(constitutive) protein, which is capable of activating transcription. These results demonstrate that NtrC(A216V) and NtrC(A220T) fail in a function of the central domain other than ATPase activity. Although they may fail in contact with sigma54-holoenzyme per se, the fact that alanine is the amino acid normally found at these positions leads us to speculate that these proteins fail in coupling energy to a change in conformation of the polymerase.
J Mol Biol 1996 Jul 19
PMID:Repressor forms of the enhancer-binding protein NrtC: some fail in coupling ATP hydrolysis to open complex formation by sigma 54-holoenzyme. 875 96

Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGF beta receptor I-III), growth factors (EGF, TGF alpha, TGF beta-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.
J Mol Med (Berl) 1996 Jan
PMID:Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. 883 68

Although the composition of the subepithelial basement membrane of the alveolar septum has been studied in detail, there is relatively little information about which cells produce it. We examined intact rat lung and isolated rat alveolar type II cells for the expression of entactin, an integral basement membrane component that binds laminin and type IV collagen. By Northern analysis, late gestation and early neonatal rat lungs expressed high levels of entactin mRNA whereas lungs from adult animals had only minimal levels of entactin mRNA. These latter findings were confirmed by in situ hybridization, which showed prominent signal for entactin mRNA in cells in the alveolar walls of neonatal animals and no signal for entactin mRNA in the alveolar walls of lungs from adult animals. The entactin mRNA throughout the alveolar walls of neonatal animals was not limited to cells that expressed surfactant-associated protein C mRNA, a marker of alveolar type II cells. Freshly harvested adult alveolar type II cells and alveolar type II cells in culture for < 6 days expressed none to minimal entactin mRNA or protein. However, with longer periods in culture, both entactin mRNA and entactin protein synthesis were evident and progressively increased. In situ hybridization indicated that >60% of the alveolar epithelial cells expressed entactin mRNA with increasing time in culture. When cultured on Engelbreth-Holm-Swarm matrix, alveolar type II cells showed the same time course of entactin mRNA expression as cells cultured on plastic. Neonatal lung mesenchymal cells produced abundant entactin in culture, consistent with the likelihood that these cells are the principal source of entactin in alveolar walls in the developing lung. These results indicate that entactin production in the normal alveolar wall occurs primarily during lung development and that mesenchymal cells are probably the principal source of production. However, because adult alveolar epithelial cells synthesize entactin in culture, it is possible that alveolar epithelium contributes to the entactin in the alveolar subepithelial basement membrane.
Am J Respir Cell Mol Biol 1996 Mar
PMID:Entactin expression by rat lung and rat alveolar epithelial cells. 884 74


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