Linked Life Data

11126362

Source:http://linkedlifedata.com/resource/pubmed/id/11126362

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
50
pubmed:dateCreated
2000-12-20
pubmed:abstractText
Apc1638N mice, which are heterozygous for a germline mutation in Apc, typically develop three to five spontaneous intestinal tumors per animal. In most cases this is associated with allelic loss of wildtype Apc. We have previously reported that the multiplicity of intestinal tumors is increased dramatically by crossing Apc1638N with an Mlh1-deficient mouse strain that represents an animal model of hereditary non-polyposis colorectal cancer (HNPCC). The increased tumor multiplicity in these mice was associated with somatic mutations in the Apc tumor suppressor gene. Here, we have examined the nature and distribution of 91 Apc mutations implicated in the development of intestinal tumors in Mlh1-/- Apc1638N animals. Protein truncation mutations were detected in a majority of tumor samples, indicating that the prevailing mechanism of Apc mutation in tumors is altered from allelic loss to intragenic mutation as a result of Mlh1 deficiency. The observed mutations were a mixture of base substitutions (27%) and frameshifts (73%). Most frameshifts were detected within dinucleotide repeats and there were prominent mutational hotspots within sequences of this sort at codons 927-929, 1209-1211 and 1461-1464. The observed Apc mutations caused protein truncation upstream of the third 20 amino acid beta-catenin binding domain and the first Axin-binding SAMP repeat, yielding Apc proteins that are predicted to be deficient in destabilizing beta-catenin. Our results reveal a characteristic mutational signature in Apc that is attributable to Mlh1 deficiency. This demonstrates a direct effect of Mlh1 deficiency in the mutation of Apc in these tumors, and provides data that clarify the role of Mlh1 in mammalian DNA mismatch repair.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
19
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5755-63
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:11126362-Adaptor Proteins, Signal Transducing, pubmed-meshheading:11126362-Adenomatous Polyposis Coli Protein, pubmed-meshheading:11126362-Alleles, pubmed-meshheading:11126362-Animals, pubmed-meshheading:11126362-Base Pair Mismatch, pubmed-meshheading:11126362-Carrier Proteins, pubmed-meshheading:11126362-Crosses, Genetic, pubmed-meshheading:11126362-Cytoskeletal Proteins, pubmed-meshheading:11126362-DNA, Neoplasm, pubmed-meshheading:11126362-DNA Mutational Analysis, pubmed-meshheading:11126362-DNA Repair, pubmed-meshheading:11126362-Dinucleotide Repeats, pubmed-meshheading:11126362-Female, pubmed-meshheading:11126362-Frameshift Mutation, pubmed-meshheading:11126362-Genes, APC, pubmed-meshheading:11126362-Germ-Line Mutation, pubmed-meshheading:11126362-Humans, pubmed-meshheading:11126362-Intestinal Neoplasms, pubmed-meshheading:11126362-Male, pubmed-meshheading:11126362-Mice, pubmed-meshheading:11126362-Mice, Inbred C57BL, pubmed-meshheading:11126362-Mutation, pubmed-meshheading:11126362-Neoplasm Proteins, pubmed-meshheading:11126362-Nuclear Proteins
pubmed:year
2000
pubmed:articleTitle
Tumor-associated Apc mutations in Mlh1-/- Apc1638N mice reveal a mutational signature of Mlh1 deficiency.
pubmed:affiliation
Strang Cancer Research Laboratory at The Rockefeller University, New York, NY 10021, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't