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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

CLN6, the gene for a variant late infantile neuronal ceroid lipofuscinosis, has been mapped to chromosome 15q21-23 by homozygosity mapping. At present the family resource consists of 31 families. By the analysis of additional polymorphic markers in this resource the critical region has been narrowed down from 12 cM to less than 4 cM. A physical map is being constructed using YAC and PAC clones as a prerequisite to transcript mapping.
Mol Genet Metab 1999 Apr
PMID:Genetic and physical mapping of the CLN6 gene on chromosome 15q21-23. 1019 Nov 23

Human TRAF-3 is a signaling molecule that interacts with the cytoplasmic tails of CD40 and other TNF-receptor family members. TRAF-3 mRNA is expressed as two major classes of approximately 2 and 8 kb and a number of TRAF-3 encoding cDNA clones differ in discrete gene segments. Because this variety of mRNA species could result from mRNA processing events and/or multiple genes, the structure and localization of TRAF-3 encoding gene elements were determined. FISH and radiation hybrid mapping demonstrated that TRAF-3 is located at chromosome 14q32.3, approximately 1 Mb centromeric to the Ig heavy chain gene complex. Physical mapping of four overlapping genomic PAC clones established that TRAF-3 transcripts are encoded by a single gene, comprised of 13 exons and spanning 130 kb. Alternative polyadenylation in the mRNA segment encoded by exon 12 accounts for the difference between the 2 kb and the 8 kb classes of transcripts. Alternative mRNA splicing in the coding region (encoded by exons 3-12) generates transcripts which delete exons 8 (75 nt), 7+8 (156 nt) or 8+9 (168 nt) and that encode distinct protein isoforms (delta25, delta52 and delta56 aa, respectively). Alternative splicing of exon 2 (139 nt) and alternative transcriptional initiation result in mRNA species with distinct 5'UTRs. Together, these data indicate that a single TRAF-3 gene encodes a variety of mRNA species by a combination of alternative polyadenylation, alternative mRNA splicing and/or alternative initiation.
Mol Immunol 1998 Dec
PMID:A single gene for human TRAF-3 at chromosome 14q32.3 encodes a variety of mRNA species by alternative polyadenylation, mRNA splicing and transcription initiation. 1019 93

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

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

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

The most common etiology for Prader-Willi syndrome and Angelman syndrome is de novo interstitial deletion of chromosome 15q11-q13. Deletions and other recurrent rearrangements of this region involve four common 'hotspots' for breakage, termed breakpoints 1-4 (BP1-BP4). Construction of an approximately 4 Mb YAC contig of this region identified multiple sequence tagged sites (STSs) present at both BP2 and BP3, suggestive of a genomic duplication event. Interphase FISH studies demonstrated three to five copies on 15q11-q13, one copy on 16p11.1-p11.2 and one copy on 15q24 in normal controls, while analysis on two Class I deletion patients showed loss of approximately three signals at 15q11-q13 on one homolog. Multiple FISH signals were also observed at regions orthologous to both human chromosomes 15 and 16 in non-human primates, including Old World monkeys, suggesting that duplication of this region may have occurred approximately 20 million years ago. A BAC/PAC contig for the duplicated genomic segment (duplicon) demonstrated a size of approximately 400 kb. Surprisingly, the duplicon was found to contain at least seven different expressed sequence tags representing multiple genes/pseudogenes. Sequence comparison of STSs amplified from YAC clones uniquely mapped to BP2 or BP3 showed two different copies of the duplicon within BP3, while BP2 comprised a single copy. The orientation of BP2 and BP3 are inverted relative to each other, whereas the two copies within BP3 are in tandem. The presence of large duplicated segments on chromosome 15q11-q13 provides a mechanism for homologous unequal recombination events that may mediate the frequent rearrangements observed for this chromosome.
Hum Mol Genet 1999 Jun
PMID:Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). 1033 34

Exit from mitosis in eukaryotic cells is regulated by the cyclosome (also called anaphase promoting complex or APC), a multisubunit ubiquitin ligase that acts on mitotic cyclins. Previous studies in a cell-free system from clam oocytes have shown that the activation of the cyclosome at the end of mitosis involves its phosphorylation by protein kinase Cdk1/cyclin B. Genetic and biochemical studies have furthermore indicated that cyclosome activity also requires a WD-40 repeat containing protein called Fizzy (FZY) or Cdc20. It has been suggested [Fang et al. (1998) Mol. Cell 2, 163-171] that in the presence of FZY, the phosphorylation of the cyclosome is not critical for its activation. By contrast, we find that the activity of the interphase, non-phosphorylated form of the cyclosome from clam embryos is not stimulated by FZY to a significant extent. However, when interphase cyclosome is first incubated with protein kinase Cdk1/cyclin B, the subsequent supplementation of FZY greatly stimulates its cyclin-ubiquitin ligase activity. Furthermore, phosphatase treatment of purified mitotic cyclosome prevents its stimulation by FZY, a process that can be reversed by the action of protein kinase Cdk1/cyclin B. We conclude that in the early embryonic cell cycles, the primary event in the activation of the cyclosome at the end of mitosis is its Cdk1-dependent phosphorylation and activation by FZY takes place in a subsequent process.
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PMID:Phosphorylation of the cyclosome is required for its stimulation by Fizzy/cdc20. 1038 65

Critical steps in the methodology of mutation analysis on routinely fixed, paraffin-embedded samples have been evaluated, including extraction and purification of DNA, amplification of gene fragments in various sizes, and screening for mutations. The DNA was extracted from tissue sections with proteinase K, using various procedures, and purified. The mutation cluster region of the APC gene was amplified with polymerase chain reaction to generate either two large or four small overlapping DNA fragments. The GC-clamped fragments were screened for mutations with temperature gradient gel electrophoresis, and mutations were identified with sequencing. The DNA was easily amplified as large fragments from fresh or unfixed-frozen samples. However, DNA amplification of large fragments from archival samples was successful in only 40 of the 114 tumor specimens analyzed (35%). Prolonged extraction, either at 55 degrees C or at 37 degrees C, gave no better results. Polymerase chain reaction of smaller fragments, with sizes between 200 and 270 base pairs (bp), was successful for 97% of the amplification reactions when using DNA that was purified with silica. Screening with temperature gradient gel electrophoresis was reproducible and sensitive with a detection limit of 5% mutated DNA in the presence of an excess of wild-type DNA.
Diagn Mol Pathol 1999 Mar
PMID:Optimizing the APC gene mutation analysis in archival colorectal tumor tissue. 1040 88

To construct the PAC and cosmid contig map spanning the HOXA cluster on human chromosome 7, we used 9 DNA markers (D7S2243, D7S3010, HOXA1, EVX1, 750, pBH8, p60, p8.0, and HOXA11), among which the final 4 were generated in this study by shotgun cloning strategy. From the libraries, 5 PAC and 35 cosmid clones were screened and as a result, an overlapping continuous array of cosmid and PAC clones covering the genomic region (about 200 kb) spanning the entire cluster were constructed. The isolated cosmids contained several consecutive HOX genes of regional group, probably sharing the regulatory processes such as alternative splicing or polyadenylation, and thus could be used as useful materials for elucidating the molecular mechanism of HOX gene expression in the future.
Somat Cell Mol Genet 1998 Jul
PMID:PAC and cosmid contig spanning the HOXA cluster on human chromosome 7p15. 1041 Jun 78


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