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)

The Schizosaccharomyces pombe dim1(+) gene is required for entry into mitosis and for chromosome segregation during mitosis. To further understand dim1p function, we undertook a synthetic lethal screen with the temperature-sensitive dim1-35 mutant and isolated lid (for lethal in dim1-35) mutants. Here, we describe the temperature-sensitive lid1-6 mutant. At the restrictive temperature of 36 degrees C, lid1-6 mutant cells arrest with a "cut" phenotype similar to that of cut4 and cut9 mutants. An epitope-tagged version of lid1p is a component of a multiprotein approximately 20S complex; the presence of lid1p in this complex depends upon functional cut9(+). lid1p-myc coimmunoprecipitates with several other proteins, including cut9p and nuc2p, and the presence of cut9p in a 20S complex depends upon the activity of lid1(+). Further, lid1(+) function is required for the multiubiquitination of cut2p, an anaphase-promoting complex or cyclosome (APC/C) target. Thus, lid1p is a component of the S. pombe APC/C. In dim1 mutants, the abundances of lid1p and the APC/C complex decline significantly, and the ubiquitination of an APC/C target is abolished. These data suggest that at least one role of dim1p is to maintain or establish the steady-state level of the APC/C.
Mol Cell Biol 1999 Apr
PMID:The schizosaccharomyces pombe dim1(+) gene interacts with the anaphase-promoting complex or cyclosome (APC/C) component lid1(+) and is required for APC/C function. 1008 19

Background: The I1307K (T3920 --> A) variant of the APC gene has been identified as a potential risk factor for colorectal cancer and is present in 6% of Ashkenazi Jews. Screening for this mutation may allow identification of people at elevated risk who would benefit from increased surveillance. Methods and Results: We designed an assay to detect the T3920 --> A allele using a primer mismatched at the 3 < 9 terminal nucleotide in the polymerase chain reaction (PCR) to generate a recognition site for the restriction enzyme Mse I. After optimization of the PCR for magnesium ion concentration and annealing temperature, the amplicon did not cut completely with the restriction enzyme in each of four tested DNAs. Sequence analysis of the PCR product that was resistant to digestion revealed that the T3920 --> A variant was not present. The artifact was caused by a single nucleotide loop-out in the genomic DNA template under the 3 < 9 region of the primer, which allowed the 3 < 9 terminal base of the primer to hybridize properly. As a result, the mismatched primer created a modified product different from that originally planned. At a magnesium ion concentration below the optimum for product yield, most of the product was digested by Mse I. Sequence analysis showed that, under these conditions, the intended product was produced. Conclusions: Mismatched primers can produce unintended products in a PCR due to looping out of a nucleotide in the template or the primer. The magnesium ion concentration can influence the sequence and amount of the product.
Mol Diagn 1998 Sep
PMID:An Unexpected Product From Polymerase Chain Reaction-Mediated Site-Directed Mutagenesis Due to Misalignment of the Mismatched Primer. 1008 73

We examined 36 cases of human sporadic colon carcinoma and corresponding normal tissue samples to evaluate loss of heterozygosity at the APC and DCC tumor suppressor genes loci using restriction fragment length polymorphism polymerase chain reaction and variable nucleotide tandem repeat analysis. Observed informativity was 83% for APC and 75% for DCC. DNA from 6 (20%) of 30 informative tumors exhibited loss of heterozygosity at the APC locus. Loss of heterozygosity at the DCC locus was observed in 7 (26%) of 27 informative tumor DNAs. Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression.
J Mol Med (Berl) 1999 Mar
PMID:Loss of heterozygosity of APC and DCC tumor suppressor genes in human sporadic colon cancer. 1009 May 94

Inherited thrombophilia due to activated protein C resistance is now recognized as one of the major genetic risk factors in the development of venous thromboembolic disease. Activated protein C resistance is secondary to a point mutation in the factor V gene, factor V Leiden. The high prevalence of this mutation in the general population, mainly in Caucasians of European descent, is a major contributing factor to the high incidence of venous thromboembolic disease in the United States, affecting one in 1000 individuals annually. Heterozygosity and homozygosity for factor V Leiden increase the risk for thrombosis 5- to 10-fold and 50- to 100-fold, respectively, compared with genotypically normal individuals. Factor V Leiden is more common than all other known genetic risk factors for thrombosis, and its presence results in a compounded risk in patients with simultaneous inherited abnormalities such as protein C, protein S, antithrombin III deficiencies, hyperhomocysteinemia, and/or acquired risk factors. Therefore, detection of activated protein C resistance and genotyping for factor V Leiden are important for establishing risk for thrombosis and ultimately for patient management.
Mol Diagn 1998 Mar
PMID:Inherited Thrombophilia due to Factor V Leiden Mutation. 1009 58

Recent evidence suggests that the beta-catenin gene (CTNNB1) acts as an oncogene, and some human colon tumors with an intact APC gene have activating mutations in CTNNB1. In this study, mutations in the region corresponding to N-terminal phosphorylation sites (codons 1-51) of the rat Ctnnb1 gene were investigated in 20 colon tumors associated with ulcerative colitis and induced with methylazoxymethanol acetate and 1-hydroxyanthraquinone. Ninety percent (18 of 20) of the tumors induced in male F344 rats harbored mutations, which were detected in three of four adenomas (75%) and 15 of 16 adenocarcinomas (94%). Of 18 total missense mutations, 13 (72%) were G-->A transitions at position 101, three were G-->A transitions at position 94, and two were C-->T transitions at position 122, resulting in the amino acid substitutions Gly34-->Glu, Asp32-->Asn, and Thr41-->Ile, respectively. Although there were no mutations in the Apc gene, as we previously reported in the same tumor samples, the results obtained in this study strongly implicate the Apc-beta-catenin-T-cell factor (Tcf) signaling pathway in methylazoxymethanol acetate, 1-hydroxyanthraquinone-induced colon carcinogenesis.
Mol Carcinog 1999 Mar
PMID:Frequent mutations of the rat beta-catenin gene in colon cancers induced by methylazoxymethanol acetate plus 1-hydroxyanthraquinone. 1020 8

Pathogenic Yersinia species are associated with both localized and systemic infections in mammalian hosts. In this study, signature-tagged transposon mutagenesis was used to identify Yersinia enterocolitica genes required for survival in a mouse model of infection. Approximately 2000 transposon insertion mutants were screened for attenuation. This led to the identification of 55 mutants defective for survival in the animal host, as judged by their ability to compete with the wild-type strain in mixed infections. A total of 28 mutants had transposon insertions in the virulence plasmid, validating the screen. Two of the plasmid mutants with severe virulence defects had insertions in an uncharacterized region. Several of the chromosomal insertions were in a gene cluster involved in O-antigen biosynthesis. Other chromosomal insertions identified genes not previously demonstrated as being required for in vivo survival of Y. enterocolitica. These include genes involved in the synthesis of outer membrane components, stress response and nutrient acquisition. One severely attenuated mutant had an insertion in a homologue of the pspC gene (phage shock protein C) of Escherichia coli. The phage shock protein operon has no known biochemical or physiological function in E. coli, but is apparently essential for the survival of Y. enterocolitica during infection.
Mol Microbiol 1999 Apr
PMID:Identification of Yersinia enterocolitica genes affecting survival in an animal host using signature-tagged transposon mutagenesis. 1021 59

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

A heterozygous GTG to ATG (Val297Met) mutation was detected in a patient with inherited protein C deficiency and deep vein thrombosis. Cosegregation of the mutation with protein C deficiency was observed through a family pedigree study. Molecular models of the serine protease domains of wild type and mutant protein C were constructed by standard comparative method. Val 297 was found to be located in the hydrophobic core of the protein. Although the substitution of Met for Val does not greatly alter the hydrophobicity of the protein, it introduces a bulkier side chain, which yields steric hindrance between this residue and adjacent residues, such as Met364, Tyr393, Ile321, Ile323, and Val378. It seems that the Met can not fit into the tight packing into which it is trapped, thereby probably inducing misfolding and/or greater instability of the protein. Such misfolding and/or instability thereby eventually disturbs the catalytic triad, in consistent with the observed type I deficiency state.
Exp Mol Med 1999 Mar 31
PMID:A molecular model of a point mutation (Val297Met) in the serine protease domain of protein C. 1023 Oct 23

In response to activation of the Wnt signaling pathway, beta-catenin accumulates in the nucleus, where it cooperates with LEF/TCF (for lymphoid enhancer factor and T-cell factor) transcription factors to activate gene expression. The mechanisms by which beta-catenin undergoes this shift in location and participates in activation of gene transcription are unknown. We demonstrate here that beta-catenin can be imported into the nucleus independently of LEF/TCF binding, and it may also be exported from nuclei. We have introduced a small deletion within beta-catenin (Delta19) that disrupts binding to LEF-1, E-cadherin, and APC but not axin. This Delta19 beta-catenin mutant localizes to the nucleus because it may not be efficiently sequestered in the cytoplasm. The nuclear localization of Delta19 definitively demonstrates that the mechanisms by which beta-catenin localizes in the nucleus are completely independent of LEF/TCF factors. beta-Catenin and LEF-1 complexes can activate reporter gene expression in a transformed T-lymphocyte cell line (Jurkat) but not in normal T lymphocytes, even though both factors are nuclear. Thus, localization of both factors to the nucleus is not sufficient for activation of gene expression. Excess beta-catenin can squelch reporter gene activation by LEF-1-beta-catenin complexes but not activation by the transcription factor VP16. Taken together, these data suggest that a third component is necessary for gene activation and that this third component may vary with cell type.
Mol Cell Biol 1999 Jun
PMID:Nuclear localization and formation of beta-catenin-lymphoid enhancer factor 1 complexes are not sufficient for activation of gene expression. 1033 Jan 89

Protein C inhibitor (PCI) has been found in seminal plasma and is considered to protect intact surrounding cells and seminal plasma proteins from possible proteolytic damage. In the present study, we showed that although the antigenic levels of PCI in two seminal plasma samples from patients with infertility were normal or slightly elevated, their inhibitory activities toward urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were absent. In contrast, uPA and tPA proteolytic activities in these two samples were 20-60-fold higher than that from normal volunteers. A time-course analysis of PCI-uPA complex formation showed that >80% of the complex had been formed within 15 min in normal seminal plasma in the presence of heparin, compared with the total complex formed after 150 min incubation, whereas no response to heparin stimulation was observed in the assays with the two patient samples. Similarly, >90% of PCI-tPA complex was formed after 30 min of heparin stimulation in normal seminal plasma but no response was observed in the two patient samples. Kinetic assays of PCI inhibitory function in the presence of activated protein C (APC) showed that PCI inhibitory activity in the two patient samples was absent and not stimulated by heparin. Western blotting also showed that most of the intact PCI molecules, in normal samples, formed complexes with either uPA or tPA but there was no complex formed in one of the two patient samples and very little complex was observed in the other, suggesting that PCI in the two patient samples is inactive. These results suggest that the presence of functionally inactive PCI in seminal plasma may be associated with infertility.
Mol Hum Reprod 1999 Jun
PMID:Functionally inactive protein C inhibitor in seminal plasma may be associated with infertility. 1034 Sep 97


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