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)

A previously uncharacterized yeast gene (YER016w) that we have named BIM1 (binding to microtubules) was obtained from a two-hybrid screen of a yeast cDNA library using as bait the entire coding sequence of TUB1 (encoding alpha-tubulin). Deletion of BIM1 results in a strong bilateral karyogamy defect, hypersensitivity to benomyl, and aberrant spindle behavior, all phenotypes associated with mutations affecting microtubules in yeast, and inviability at extreme temperatures (i.e., >/=37 degrees C or </=14 degrees C). Overexpression of BIM1 in wild-type cells is lethal. A fusion of Bim1p with green fluorescent protein that complements the bim1Delta phenotypes allows visualization in vivo of both intranuclear spindles and extranuclear microtubules in otherwise wild-type cells. A bim1 deletion displays synthetic lethality with deletion alleles of bik1, num1, and bub3 as well as a limited subset of tub1 conditional-lethal alleles. A systematic study of 51 tub1 alleles suggests a correlation between specific failure to interact with Bim1p in the two-hybrid assay and synthetic lethality with the bim1Delta allele. The sequence of BIM1 shows substantial similarity to sequences from organisms across the evolutionary spectrum. One of the human homologues, EB1, has been reported previously as binding APC, itself a microtubule-binding protein and the product of a gene implicated in the etiology of human colon cancer.
Mol Biol Cell 1997 Dec
PMID:BIM1 encodes a microtubule-binding protein in yeast. 939 84

A rat model for human ulcerative colitis (UC) has been developed by using 1-hydroxyanthraquinone (1-HA) to cause severe inflammation of colonic mucosa. 1-HA also has synergistic effects on the carcinogenicity of methylazoxymethanol (MAM) acetate in the rat colon. In this study, four adenomas and 16 adenocarcinomas induced in male F344 rats by 1-HA and MAM acetate were examined for mutations in the entire coding regions and introns flanking coding exons of the APC gene by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and PCR-restriction-SSCP analyses. No mutations were found. These results, together with our previous observations of a relative lack of Ki-ras gene mutations in the same tumors, are similar to those found in human UC-associated colon cancer, suggest a common pathway in these two systems, although they are different in their implication of p53 mutations. Therefore, this model may have some relevance and application to the study of colon cancer in human inflammatory bowel disease, which is not associated with APC mutations or with Ki-ras or p53 mutations.
Mol Carcinog 1997 Dec
PMID:No involvement of APC gene mutations in ulcerative colitis-associated rat colon carcinogenesis induced by 1-hydroxyanthraquinone and methylazoxymethanol acetate. 943 83

Factor V Leiden (FVL) refers to a mutation on the clotting factor, Factor V. Protein C is a factor involved in the fibrinolytic pathway. Activated protein C (APC) normally degrades activated Factor V. The presence of the Leiden mutation on Factor V makes this protein resistant to degradation by APC, leading to a hypercoagulable state. Previous studies reported a prevalence of FVL in various populations between 0-6% and absent in Africans. We studied two factor V alleles from one hundred random blood samples submitted for CBC. DNA was extracted, PCR was performed for wild-type allele and Leiden mutation with GH internal control for both reactions, and agarose gel electrophoresis was performed. Of 100 samples, five were heterozygous for FVL, which is in accord with other reports. Interestingly, four of 70 samples (5.8%) from African-Americans were positive for the mutation. The study indicates an apparent prevalence of 5% in the Newark, New Jersey population, including African-Americans.
Res Commun Mol Pathol Pharmacol 1998 Mar
PMID:Prevalence of factor V Leiden in African-Americans. 959 28

The transcription activator protein NtrC (nitrogen regulatory protein C) can catalyze the transition of E. coli RNA polymerase complexed with the sigma54 factor (RNAP.sigma54) from the closed complex (RNAP.sigma54 bound at the promoter) to the open complex (melting of the promoter DNA). This process involves phosphorylation of NtrC, assembly of a multimeric NtrC complex at the enhancer DNA sequence, interaction of this complex with promoter bound RNAP. sigma54 via DNA looping, and hydrolysis of ATP. We have used analytical ultracentrifugation to study the different NtrC association states and to derive hydrodynamic models for the conformation of the various NtrC species. The following results were obtained. (i) The unphosphorylated wild-type protein formed a dimer with a measured molecular weight of 102(+/-3) kDa, which compares to a calculated molecular weight of 54 kDa for a monomer (concentration range studied 2 to 8 microM NtrC monomer). (ii) In the unphosphorylated state one NtrC dimer was bound to one binding site as determined with DNA oligonucleotide duplexes containing one or two binding sites (concentration range studied 50 to 1000 nM NtrC dimer). (iii) The data obtained at protein concentrations that were below the concentration of binding sites indicate that binding to the DNA duplex with two binding sites occurred with essentially no cooperativity. The experiments were conducted in the absence of ATP. (iv) The phosphorylated protein formed a specific complex at the DNA duplex with the enhancer sequence (two NtrC binding sites) that consisted of four dimers (concentration range studied 100 to 1000 nM NtrC dimer). (v) The formation of this octameric complex was highly cooperative, and the data suggest that two DNA strands could bind simultaneously to this complex. (vi) From the sedimentation data a model was derived in which the NtrC dimer adopts a V shaped structure with the DNA binding domains being located at the bottom and the two receiver domains at the top of the V. In this conformation higher order NtrC complexes can be stabilized by interaction between the phosphorylated receiver domain and the central activation domain of different NtrC dimers.
J Mol Biol 1998 May 22
PMID:Association states of the transcription activator protein NtrC from E. coli determined by analytical ultracentrifugation. 960 Aug 53

A single factor V gene G-A mutation (Arg506Gln) underlying activated protein C (APC) resistance is a common risk factor for venous thromboembolism. It is still unclear whether the factor V Leiden predisposes patients to arterial thrombosis and myocardial infarction (MI). To determine a correlation between the factor V Leiden mutation and MI in different age categories, DNA samples from 287 patients with "early" and "late" MI were investigated. As control groups 373 young subjects (mean age 11 years) and 110 elderly ones (mean age 80 years) were studied. We found a significant difference in mutant allele distribution in the "late" MI group compared to the "early" MI group (chi2 = 9.86, OR = 13,7, P < 0.005) and the control group of elderly subjects (chi2 = 5.92, OR = 8.6, P < 0.02). The mean age of MI patients carrying the Leiden mutation was 72 years, i.e., 12 years higher than the mean age of all investigated MI patients (60 years). Thus, we found a statistically significant correlation between MI and factor V Leiden mutation in elderly subjects.
Mol Genet Metab 1998 Jun
PMID:Age as a risk factor for myocardial infarction in Leiden mutation carriers. 970 41

Several extracellular modular proteins, including proteases of the complement and blood coagulation cascades, are shown here to exhibit conserved sequence patterns specific for a particular module-domain association. This was detected by comparative analysis of sequence variability in different multiple sequence alignments, which provides a new tool to investigate the evolution of modular proteins. A first example deals with the proteins featuring a common complement control protein (CCP) module-serine protease (SP) domain pattern at their C-terminal end, defined here as the CCP-SP sub-family. These proteins include the complement proteases C1r, C1s and MASPs, the Limulus clotting factor C, and the proteins of the haptoglobin family. A second example deals with blood coagulation factors VII, IX and X and protein C, all featuring a common epidermal growth factor (EGF)-SP C-terminal assembly. Highly specific motifs are found at the connection between the CCP or EGF module and the activation peptide of the SP domain: [P/A]-x-C-x-[P/A]-[I/V]-C-G-x-[P/S/K] in the case of the CCP-SP proteins, and C-x-[P/S]-x-x-x-[Y/F]-P-C-G in the case of the EGF-SP proteins. Each motif is strictly conserved in the whole sub-family and it is detected in no more than one other known protein sequence. Strikingly, most of the conserved residues specific to each sub-family appear to be clustered at the interface between the SP domain and the CCP or EGF module. We propose that a rigid module-domain interaction occurs in these proteins and has been conserved through evolution. The functional implications of these assemblies, underlined by such evolutionary constraints, are discussed.
J Mol Biol 1998 Sep 18
PMID:Evolutionary conserved rigid module-domain interactions can be detected at the sequence level: the examples of complement and blood coagulation proteases. 973

Surprisingly, although highly temperature-sensitive, the bimA1(APC3) anaphase-promoting complex/cyclosome (APC/C) mutation does not cause arrest of mitotic exit. Instead, rapid inactivation of bimA1(APC3) is shown to promote repeating oscillations of chromosome condensation and decondensation, activation and inactivation of NIMA and p34(cdc2) kinases, and accumulation and degradation of NIMA, which all coordinately cycle multiple times without causing nuclear division. These bimA1(APC3)-induced cell cycle oscillations require active NIMA, because a nimA5 + bimA1(APC3) double mutant arrests in a mitotic state with very high p34(cdc2) H1 kinase activity. NIMA protein instability during S phase and G2 was also found to be controlled by the APC/C. The bimA1(APC3) mutation therefore first inactivates the APC/C but then allows its activation in a cyclic manner; these cycles depend on NIMA. We hypothesize that bimAAPC3 could be part of a cell cycle clock mechanism that is reset after inactivation of bimA1(APC3). The bimA1(APC3) mutation may also make the APC/C resistant to activation by mitotic substrates of the APC/C, such as cyclin B, Polo, and NIMA, causing mitotic delay. Once these regulators accumulate, they activate the APC/C, and cells exit from mitosis, which then allows this cycle to repeat. The data indicate that bimAAPC3 regulates the APC/C in a NIMA-dependent manner.
Mol Biol Cell 1998 Nov
PMID:Regulation of the anaphase-promoting complex/cyclosome by bimAAPC3 and proteolysis of NIMA. 980 93

Recent studies on human protein C gene expression have revealed the presence of three transcription factor binding sites in close proximity to the transcription start site. Binding sites for the liver-enriched hepatocyte nuclear factors 1 and 3 (HNF-1 and HNF-3, respectively) are located immediately upstream of the transcription start site, whereas just downstream of the start site a presently unidentified transcription factor may bind. To identify other candidate transcription factor binding sites in the protein C promoter, we studied the promoter sequence identity in a number of evolutionarily close and more distant species: Gorilla gorilla, Pongo pygmaeus, Pan troglodytes, Homo sapiens, Cebus apella, Macaca mulatta, Callithrix jacchus, Papio hamadryas, Macaca fascicularis, and Rattus norvegicus. This analysis showed that a high degree of identity (78%) exists among the different primates. Comparison of the primate consensus sequence with the Rattus norvegicus protein C promoter sequence revealed the presence of seven identical regions (I to VII). Two of these regions overlap with established regulatory sequences for HNF-3 and HNF-1 (region VI) and for PCE-1 (region VII), respectively. The functional importance and the transcription factors that may bind to the other five identical regions are now to be determined.
J Mol Evol 1998 Dec
PMID:Identification of evolutionarily invariant sequences in the protein C gene promoter. 984 7

Microsatellite instability and allelic deletions of tumor suppressor genes have been observed frequently in tumors. Molecular pathogenesis of the development of dysplasia and carcinoma in ulcerative colitis is still unclear. In order to detect microsatellite alterations in ulcerative colitis, we analyzed loss of heterozygosity (LOH) and microsatellite instability (MI) on chromosomes 3, 6, 7, 12, and tumor suppressor gene loci, including p53, APC, and p16, of chronically inflamed, non-dysplastic epithelium after microdissection. Twelve of 13 (92%) cases showed LOH and/or MI at one or more loci. LOH at chromosome 3 and MI at chromosome 12 were observed in 50% and 62%, respectively. However, LOH at p53 and p16 was detected in only one case each. These results suggest that chronic inflammation may initiate microsatellite alteration, which subsequently transform ulcerative colitis to dysplasia or cancer. This finding provides information for the evaluation and treatment of patients with ulcerative colitis.
Int J Mol Med 1998 Aug
PMID:Loss of heterozygosity and microsatellite instability in non-neoplastic mucosa from patients with chronic ulcerative colitis. 985 92

Precise correlation of histomorphology with the results of molecular genetic analysis is difficult in gastric cancer tissue composed of intestinal and diffuse types. A novel microdissection procedure was applied to correlate p53 and APC allelic loss with histologic type and tumor stage (mucosal vs. invasive cancer) in formalin-fixed, paraffin-embedded specimens of 25 gastric cancers. In addition, mucosal and invasive lesions were dissected from each of 11 invasive gastric cancers to study progression, and allelic loss of the p53 and APC genes was assessed. The p53 gene underwent loss of heterozygosity (LOH) in 4 of 4 informative cases of intestinal-type gastric cancer with mucosal lesions associated with invasion. By contrast, no p53 LOH was found among 6 informative cases with mucosal cancer. LOH of the APC gene in both intestinal and diffuse types of cancer was detected in 4 of 7 and 5 of 6 informative cases, respectively. These data suggest that allelic deletion of the p53 gene in intestinal-type gastric carcinoma predicts the invasive potential of mucosal cancer, and that inactivation of the APC gene plays a role in the genetic tumorigenesis of both intestinal and diffuse types of gastric cancer. Microdissection can correlate genetic alterations with histologic morphology in gastric cancer.
Diagn Mol Pathol 1998 Oct
PMID:Correlation of histologic morphology and tumor stage with molecular genetic analysis using microdissection in gastric carcinomas. 999 Apr 80


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