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)

This study evaluated the potential contribution of the APC gene to malignant transformation in patients with renal cell carcinoma. We tested 36 human renal cell carcinoma samples and 18 adjacent normal kidney tissues for the expression of APC protein, both wild and truncated types, by western blot using antibodies that recognize either the carboxy or the amino epitope of the APC protein. The same tumor samples together with autologous peripheral blood were also analyzed at the DNA level. Using specific oligonucleotide primers for exons 11 and 15, gene instability was followed by polymerase chain reaction/loss of heterozygosity (LOH) (on the basis of restriction fragment length polymorphism). Molecular data were also compared to pathohistological diagnosis, TNM stage, and patient's age using multivariate statistical methods. All normal renal tissues revealed expression of the wild-type APC protein. Neither wild nor mutant type proteins were found in 36% (13/36) of tumor samples; the rest of tumor tissues expressed the wild-type protein (312 kDa). Mutated APC protein, with a molecular weight of 117 kDa, was found in only one tumor sample. From 36 tumor samples 16 (44.4%) were informative for RsaI exon 11 polymorphic site, while only half of these (8/16) demonstrated LOH. From 13 tumor samples that had no detectable protein product by western blot analysis eight were homozygous for the exon 11 polymorphism and were tested for another polymorphic site, MspI/exon 15. The overall proportion of LOH cases for both polymorphisms tested was 52.9% (9/17). Pathohistological diagnosis and molecular data showed no correlation. However, multivariate analysis determined a stage strong positive correlation of age and TNM with the presence of LOH and the absence of the wild-type APC protein. Out results suggest that the APC tumor suppressor gene plays a role in renal carcinogenesis. Alterations in this gene are responsible for tumor evolution and progression, but cannot be considered as a first event in tumor initiation.
J Mol Med (Berl) 1999 May
PMID:Loss of heterozygosity and protein expression of APC gene in renal cell carcinomas. 1042 94

We have mapped and sequenced the region immediately centromeric of the human major histocompatibility complex (MHC). A cluster of 13 genes/pseudogenes was identified in a 175 kb PAC linking the TAPASIN locus with the class II region. It includes two novel human genes (BING4 and SACM2L) and a thus far unnoticed human leucocyte antigen (HLA) class II pseudogene, termed HLA-DPA3. Analysis of the G+C content revealed an isochore boundary which, together with the previously reported telomeric boundary, defines the MHC class II region as one of the first completely sequenced isochores in the human genome. Comparison of the sequence with limited sequence from other cell lines shows that the high sequence variation found within the classical class II region extends beyond the identified isochore boundary leading us to propose the concept of an "extended MHC". By comparative analysis, we have precisely identified the mouse/human synteny breakpoint at the centromeric end of the extended MHC class II region between the genes HSET and PHF1.
J Mol Biol 1999 Aug 27
PMID:Gene organisation, sequence variation and isochore structure at the centromeric boundary of the human MHC. 1045 89

Background: Resistance to activated protein C(APC) is the most prevalent identifiable risk factor for inherited thrombophilia. Over 90% of APC resistance results from a single point mutation in the Factor V gene. The mutation, termed FV R506Q of FV Leiden, predicts an abnormal Factor Va protein in which arginine, at amino acid position 506, is replaced by glutamine, rendering Factor Va resistant to proteolytic inactivation by APC, thus establishing a life long hypercoagulable state. The current study compared three different polymerase chain reaction (PCR)-based approaches for the detection of FV R506Q. Methods and Results: Sixty-seven patient blood samples were genotyped by (1) analyzing for loss of a Mnl I recognition site, an acquired restriction-fragment-length polymorphism (RFLP) due to FV R506Q; (2) primer-engineered RFLP wherein the presence of FV R506Q results in generation of a novel Nla III recognition site; and (3) allele-specific PCR. Sixty-five of 67 patient samples yielded concordant genotype results by all three PCR methods. Of the remaining 2 of the 67 patients, a "nondiagnostic" result was obtained for either allele-specific PCR or primer-engineered RFLP. Conclusions: A comparative analysis of 67 patient samples demonstrated that primer engineered RFLP and allele-specific PCR offer feasible alternative or confirmatory testing approaches to Mnl I RFLP for the detection of FV R506Q. A high degree of diagnostic concordance was observed for all three methods, and no false positive or negative results were observed with the Mnl I RFLP technique.
Mol Diagn 1996 Dec
PMID:Resistance to Activated Protein C: Comparison of Three Different PCR Methods for Detection FV R506Q. 1046 76

In Wnt signaling, beta-catenin and plakoglobin transduce signals to the nucleus through interactions with TCF-type transcription factors. However, when plakoglobin is artificially engineered to restrict it to the cytoplasm by fusion with the transmembrane domain of connexin (cnxPg), it efficiently induces a Wnt-like axis duplication phenotype in Xenopus. In Xenopus embryos, maternal XTCF3 normally represses ventral expression of the dorsalizing gene Siamois. Two models have been proposed to explain the Wnt-like activity of cnxPg: 1) that cnxPg inhibits the machinery involved in the turnover of cytosolic beta-catenin, which then accumulates and inhibits maternal XTCF3, and 2) that cnxPg directly acts to inhibit XTCF3 activity. To distinguish between these models, we created a series of N-terminal deletion mutations of cnxPg and examined their ability to induce an ectopic axis in Xenopus, activate a TCF-responsive reporter (OT), stabilize beta-catenin, and colocalize with components of the Wnt signaling pathway. cnxPg does not colocalize with the Wnt pathway component Dishevelled, but it does lead to the redistribution of APC and Axin, two proteins involved in the regulation of beta-catenin turnover. Expression of cnxPg increases levels of cytosolic beta-catenin; however, this effect does not completely explain its signaling activity. Although cnxPg and Wnt-1 stabilize beta-catenin to similar extents, cnxPg activates OT to 10- to 20-fold higher levels than Wnt-1. Moreover, although LEF1 and TCF4 synergize with beta-catenin and plakoglobin to activate OT, both suppress the signaling activity of cnxPg. In contrast, XTCF3 suppresses the signaling activity of both beta-catenin and cnxPg. Both exogenous XLEF1 and XTCF3 are sequestered in the cytoplasm of Xenopus cells by cnxPg. Based on these data, we conclude that, in addition to its effects on beta-catenin, cnxPg interacts with other components of the Wnt pathway, perhaps TCFs, and that these interactions contribute to its signaling activity.
Mol Biol Cell 1999 Oct
PMID:Membrane-anchored plakoglobins have multiple mechanisms of action in Wnt signaling. 1051 57

Although, since the isolation of pituitary adenylate cyclase-activating polypeptide (PACAP), a wealth of literature has been published describing its localization, binding sites, and biological activities in a variety of mammalian tissues, only very little is known about PACAP in avian species. Therefore, in order to find out the sites of actions of PACAP and to elucidate its physiological significance in birds, we identified a chicken PACAP receptor homologue of the mammalian type I receptors (PAC(1)-Rs). The chicken PACAP type I cDNA sequence was obtained using reverse transcriptase-polymerase chain reaction (RT-PCR) in combination with 3'- and 5'-RACE PCR. This cDNA encodes a 471 amino acid precursor protein, sharing 81-83% sequence identity with mammalian analogs and 76% amino acid identity with the goldfish type I PACAP receptor. Northern blot analysis of chicken brain poly(A)(+)-rich RNA revealed the presence of a 5.5 kb and 7.5 kb PAC(1) receptor transcript. RT-PCR revealed that the chicken PACAP receptor is mainly expressed in the brain and gonads. A smaller amount of the receptor mRNA was found in pituitary, adrenal gland, kidney, intestine, pancreas, lung, and heart tissue. In situ hybridization with specific antisense oligodeoxynucleotide probes showed a widespread distribution of PAC(1) receptor mRNA in the chicken brain, with the highest expression being found in the dorsal telencephalon, olfactory bulb, hypothalamus, optic tectum, and cerebellar cortex. These findings suggest that PACAP affect a variety of functions both in the brain and peripheral tissues of the chicken.
Brain Res Mol Brain Res 1999 Aug 25
PMID:Molecular cloning and expression of a chicken pituitary adenylate cyclase-activating polypeptide receptor. 1052 79

The ubiquitin-dependent proteolysis of mitotic cyclin B, which is catalyzed by the anaphase-promoting complex/cyclosome (APC/C) and ubiquitin-conjugating enzyme H10 (UbcH10), begins around the time of the metaphase-anaphase transition and continues through G1 phase of the next cell cycle. We have used cell-free systems from mammalian somatic cells collected at different cell cycle stages (G0, G1, S, G2, and M) to investigate the regulated degradation of four targets of the mitotic destruction machinery: cyclins A and B, geminin H (an inhibitor of S phase identified in Xenopus), and Cut2p (an inhibitor of anaphase onset identified in fission yeast). All four are degraded by G1 extracts but not by extracts of S phase cells. Maintenance of destruction during G1 requires the activity of a PP2A-like phosphatase. Destruction of each target is dependent on the presence of an N-terminal destruction box motif, is accelerated by additional wild-type UbcH10 and is blocked by dominant negative UbcH10. Destruction of each is terminated by a dominant activity that appears in nuclei near the start of S phase. Previous work indicates that the APC/C-dependent destruction of anaphase inhibitors is activated after chromosome alignment at the metaphase plate. In support of this, we show that addition of dominant negative UbcH10 to G1 extracts blocks destruction of the yeast anaphase inhibitor Cut2p in vitro, and injection of dominant negative UbcH10 blocks anaphase onset in vivo. Finally, we report that injection of dominant negative Ubc3/Cdc34, whose role in G1-S control is well established and has been implicated in kinetochore function during mitosis in yeast, dramatically interferes with congression of chromosomes to the metaphase plate. These results demonstrate that the regulated ubiquitination and destruction of critical mitotic proteins is highly conserved from yeast to humans.
Mol Biol Cell 1999 Nov
PMID:Cell cycle-regulated proteolysis of mitotic target proteins. 1056 81

Neurofibromatosis type 1 patients with a submicroscopic deletion spanning the NF1 tumor suppressor gene are remarkable for an early age at onset of cutaneous neurofibromas, suggesting the deletion of an additional locus that potentiates neurofibromagenesis. Construction of a 3.5 Mb BAC/PAC/YAC contig at chromosome 17q11.2 and analysis of somatic cell hybrids from microdeletion patients showed that 14 of 17 cases had deletions of 1.5 Mb in length. The deletions encompassed the entire 350 kb NF1 gene, three additional genes, one pseudogene and 16 expressed sequence tags (ESTs). In these cases, both proximal and distal breakpoints mapped at chromosomal regions of high identity, termed NF1REPs. These REPs, or clusters of paralogous loci, are 15-100 kb and harbor at least four ESTs and an expressed SH3GL pseudogene. The remaining three patients had at least one breakpoint outside an NF1REP element; one had a smaller deletion thereby narrowing the critical region harboring the putative locus that exacerbates neurofibroma development to 1 Mb. These data show that the likely mechanism of NF1 microdeletion is homologous recombination between NF1REPs on sister chromatids. NF1 microdeletion is the first REP-mediated rearrangement identified that results in loss of a tumor suppressor gene. Therefore, in addition to the germline rearrangements reported here, NF1REP-mediated somatic recombination could be an important mechanism for the loss of heterozygosity at NF1 in tumors of NF1 patients.
Hum Mol Genet 2000 Jan 01
PMID:NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. 1058 76

So far, somatic mutations of the PTEN gene have been found in several different neoplasms but not in colorectal tumours. As exons 7 and 8 of the PTEN coding sequence contain an (A)(6)repeat and mononucleotide repeat sequences are targets for mutations in tumours with microsatellite instability (MI), we screened a panel of sporadic colorectal tumours exhibiting MI to test whether PTEN gene repeats are frequently mutated in MI(+)colorectal cancers. Of 32 cases studied, seven mutations were found in six (18.75%) patients, as a PTEN biallelic frameshift mutation was observed in one case, with consequent loss of function of the gene. Loss of heterozygosity, evaluated in the remaining five cases using the microsatellite marker D10S541, was detected in two of three informative samples. To further address the role of the PTEN gene in MI(+)colorectal cancer, in the six patients with mutated PTEN, we analysed the mononucleotide repeats of six other genes: BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC. In two of these six patients, mutations of the TGFbRII gene only were present, indicating that PTEN may have a role in the mutator pathway of colorectal tumorigenesis. Overall, these results indicate that PTEN mutations are selected for during tumorigenesis in MI(+)colorectal tumours. The mutation of both PTEN alleles and evidence that the PTEN protein is expressed in normal colon suggest that loss of function of this gene could play a direct role in tumorigenesis.
Hum Mol Genet 2000 Jan 22
PMID:Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis. 1060 39

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide and its specific receptor (the PAC(1) receptor) is widely distributed in the rat brain. It has been reported that alternative splicing of the region encoding the third intracellular loop of the PAC(1) receptor generates six isoforms which are differentially coupled to signal transduction pathways, but the precise distribution and localization of these splice isoforms in the brain remain to be determined. Using the initial specific primer pairs which correspond to the 'hip' or 'hop' types of receptors for the solution-phase reverse transcription-polymerase chain reaction (RT-PCR), we demonstrated that the major splice variants of the PAC(1) receptor in various regions of the rat brain are the short splice isoform 'PAC(1)-R-s' which does not contain either the 'hip' or 'hop' cassette and the another splice isoform, 'PAC(1)-R-hop', which contains the 'hop' cassette. With an innovative molecular histochemical technique, in situ RT-PCR, we determined that these two splice isoforms are both intensely expressed in the mitral cells of the olfactory bulb, the Purkinje cells of the cerebellum, the pyramidal cells of the hippocampus and neocortex, and many neurons in the nuclei of hypothalamus and thalamus as well as other regions. The initial mapping of the cell type-specific expression of these two splice variants of the PAC(1) receptor provides the basis for a better understanding of the functional significance of the PAC(1)-R and its ligand PACAP in various brain regions.
Brain Res Mol Brain Res 2000 Jan 10
PMID:Cellular distribution of the splice variants of the receptor for pituitary adenylate cyclase-activating polypeptide (PAC(1)-R) in the rat brain by in situ RT-PCR. 1064 99

Recently, several studies have reported an association between anxiety traits, affective disorders and autism and alleles of a functional promoter polymorphism (5HTT-LPR) in the human serotonin transporter (5HTT, SERT).1-3 The mechanistic basis for allelic differences in transporter transcription are presently unknown. To explore this issue, we cloned the human 5HTT promoter region from a PAC genomic library and now describe an unreported 381-bp insert between the polymorphic region and the transcription start site. We verified the presence of this novel sequence by Southern hybridization of genomic digests and PCR amplifications from multiple unrelated individuals. Sequence analysis of the novel region reveals a number of canonical transcription factor binding sites (eg AP1, Elk1, NFkappaB) that may be important in controlling the response of the 5HTT gene to regulatory factors. PCR studies of genomic templates reveal a low level of amplification of a deleted template matching the size of the originally reported 5HTT promoter. This deleted template is absent from PAC amplifications, suggesting that the human 5HTT promoter may exhibit in vivo instability. Molecular Psychiatry (2000) 5, 110-115.
Mol Psychiatry 2000 Jan
PMID:Modified structure of the human serotonin transporter promoter. 1067 78


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