Mice homozygous for the G12D mutation are embryonic lethal. Heterozygotes have a reduced lifespan compared with wildtype controls, with a mean survival time of 200 days. All animals develop an extensive tumor burden. Most frequently, tumors are observed in the lung, where 100% of animals develop multifocal tumors first detectable as small pleural nodules at one week of age. The animals are also prone to both thymic lymphoma (30%) and skin papillomas (40%). Carcinomas of the pancreas and colon are surprisingly not observed in these mice. However, all of the mutant mice examined had multiple aberrant crypt foci (ACF) of the colon which are observed in human patients with colon cancer but absent in wild-type mice. Due to the short latency and high penetrance of the tumor phenotype, these mice may be useful in screening potential chemopreventative agents.
Dr. Tyler Jacks, Massachusetts Institute of Technology
Mice homozygous for the Kras LA2 allele are embryonic lethal. Heterozygotes have a reduced lifespan compared with wildtype controls, with a mean survival time of 200 days. All animals develop an extensive tumor burden. Most frequently, tumors are observed in the lung, where 100% of animals develop multifocal tumors first detectable as small pleural nodules at one week of age. Tumor multiplicty and size increase with age, ultimately resulting in respiratory distress and death. In addition to lung cancer, the animals are prone to both thymic lymphoma (30%) and skin papillomas (40%). The papillomas typically arise in areas subject to abrasion (ears and snout). These pedunculated papillomas demonstrate limited, if any progression to carcinomas during the lifespan of these animals. Carcinomas of the pancreas and colon are surprisingly not observed in these mice. However, all of the mutant mice examined had multiple aberrant crypt foci (ACF) of the colon which are absent in wild-type mice. Due to the short latency and high penetrance of the tumor phenotype, these mice may be useful in screening potential chemopreventative agents.
A targeting vector was designed to introduce a G12D mutation to exon 1 of the gene and place a pgk-neomycin resistance cassette in intron 1. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Animals carrying the pgk-neo cassette flanked by an insertional duplication of the G12D exon 1 mutation were selected for further study (K-rasLA2 allele). In vivo recombination/excision events between the two mutant exons occur in all carrier animals, excising the pgk-neo cassette and leaving a single G12D mutation to confer the oncogenic phenotype. This spontaneous oncogene activation closely recapitulates that found in human cancers. This line was maintained on a 129S4/SvJae genetic background by the donating laboratory.
|Allele Name||targeted mutation 3, Tyler Jacks|
|Allele Synonym(s)||K-rasLA2; KrasG12D; KrasLA2-G12D; KrasLA2; KrasLA2|
|Gene Symbol and Name||Kras, Kirsten rat sarcoma viral oncogene homolog|
|Gene Synonym(s)||AI929937; C-K-RAS; CFC2; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-ras; KI-RAS; KRAS1; KRAS2; Ki-ras; Kirsten rat sarcoma oncogene 2, expressed; Kras-2; Kras-2; Kras2; Kras2; NS; NS3; RALD; RASK2; c-Ki-ras; expressed sequence AI929937; p21|
|Promoter||Kras, Kirsten rat sarcoma viral oncogene homolog, mouse, laboratory|
|Strain of Origin||129S4/SvJae|
|Molecular Note||Insertion of the targeting vector results in a duplication of exon 1 with a neomycin resistance gene between the duplicate exons. Both copies of exon 1 contain an activating glycine to aspartic acid mutation at codon 12. In the absence of intrachromosomal recombination, this allele does not produce any protein and mutant homozygotes die during embryogenesis. In heterozygotes, when intrachromosomal recombination occurs in vivo, all of the recombination events produce an active G12D allele. Expression of G12D protein results in the formation of lung tumors and death at ~200 days (7 months).|
|Mutations Made By|| |
Dr. Tyler Jacks, Massachusetts Institute of Technology
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