This tamoxifen-inducible KPC strain may be used as a model for pancreatic ductal adenocarcinoma (PDAC).
The Jackson Laboratory
Genetic Background | Generation |
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N1F4
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Allele Type | Gene Symbol | Gene Name |
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Targeted (Conditional ready (e.g. floxed), No functional change) | Trp53 | transformation related protein 53 |
Allele Type | Gene Symbol | Gene Name |
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Targeted (Conditional ready (e.g. floxed), No functional change) | Kras | Kirsten rat sarcoma viral oncogene homolog |
Allele Type |
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Transgenic (Recombinase-expressing) |
This KPC strain is a tamoxifen-inducible model for pancreatic ductal adenocarcinoma (PDAC) carrying the Kras LSL G12D (Krastm4Tyj) allele, the Trp53tm1Brn floxed allele, and the Tg(Pdx1-cre/Esr1*)#Dam transgene. These KPC mice develop acinar-to-ductal metaplasias and pancreatic intraepithelial neoplasias (PanIN) within 8-10 weeks following tamoxifen administration, and invasive pancreatic ductal adenocarcinoma within 14-16 weeks. The time course and metastatic spread (to liver, lung, parietal peritoneum and diaphragm) is similar to the phenotype observed in the KPC model of PDAC. Histological analysis of pancreatic lesions shows the same type of multifocal tumors seen in the KPC model.
The Krastm4Tyj allele [KrasLSL-G12D] contains a point mutation (G12D) whose expression is blocked by the presence of a loxP-flanked stop codon. Mice homozygous for this Krastm4Tyj allele die in utero. Cre-mediated recombination can excise the stop codon and permit the oncogenic protein to be expressed.
The Trp53tm1Brn allele [p53LoxP] contains loxP sites flanking exons 2 through 10 of the transformation related protein 53 gene. Mice homozygous for the Trp53tm1Brn allele have a somewhat reduced fertility, but may be bred. Cre-mediated deletion of the floxed sequence results in a knock-out allele.
The Tg(Pdx1-cre/Esr1*)#Dam transgene [Pdx1-CreER] has the mouse Pdx1 promoter driving expression of a tamoxifen-inducible Cre recombinase (Cre-ERTM; Cre recombinase fused to a G525R mutant form of the mouse estrogen receptor ligand binding domain).
As described for Stock No. 024968, mice homozygous for this Pdx1-CreER transgene are viable and fertile. Immunohistochemistry demonstrates that transgene expression closely follows endogenous Pdx1 patterns. Expression is observed in acini, islet and duct cells but not in mesenchymal cells (endothelial and mesenchyme-derived smooth muscle cells) of the pancreas. Robust Cre expression can be detected by E10.5 in pancreatic epithelium.
This KrasLSL-G12D;p53LoxP;Pdx1-CreER triple mutant line was generated by crossing three single mutant strains:
B6.129S4-Krastm4Tyj/J Stock No. 008179,
B6.129P2-Trp53tm1Brn/J Stock No. 008462,
STOCK Tg(Pdx1-cre/Esr1*)#Dam/J Stock No. 024968.
For the Krastm4Tyj allele [KrasLSL-G12D], a targeting vector was designed to place a G12D point mutation in exon 1 of the gene and a loxP-flanked STOP element upstream of the mutation. The STOP element incorporates a PGK-puromycin selection cassette at the 5' end in an opposite directional orientation. An adenoviral strong splice acceptor, typically used in gene trap vectors, is fused upstream of the his3 stuffer fragment to prevent splicing around the stopper (in the case that transcription isn't completely silenced). A mutant splice donor site is on the 3' end and a tetrameric tandem array of SV40 PolyA. The stopper was designed to fit into genomic Sal1 or Xho1 sites. The stop cassette prevents the expression of mutant Kras until it is removed by Cre mediated recombination of the Loxp sites, thus allowing expression of oncogenic Kras. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. This strain was backcrossed to C57BL/6 for more than 10 generations by the donating laboratory which verified correct orientation by Southern assays involving 5' and 3' external and internal probes.
For the Trp53tm1Brn mutation [p53LoxP or p53flox], a targeting vector was used to introduce flanking loxP sites to introns 1 and 10 of the gene. An IB10/E14IB10 129P2/OlaHsd-derived embryonic stem cell line was used to create the mutation. The mice were then backcrossed to C57BL/6 for eight generations.
For the Tg(Pdx1-cre/Esr1*)#Dam transgene [Pdx1-CreER], a Cre-ERTM sequence (Cre recombinase fused to a G525R mutant form of the mouse estrogen receptor ligand binding domain) was introduced to the starting ATG of mouse Pdx1, and followed by an SV40 polyadenylation signal. The transgenic vector was injected into B6CBAF1 embryos. Resultant mice were originally crossed with outbred ICR or CD1 animals, then backcrossed to C57BL/6. Subsequent crosses to both ICR/CD1 and C57BL/6 contribute to the STOCK background.
Expressed Gene | cre/Esr1, Cre recombinase and estrogen receptor 1 fusion gene, |
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Site of Expression | Tamoxifen induction drives mosaic expression of cre recombinase in endocrine, exocrine, and duct tissue of the pancreas. |
Allele Name | targeted mutation 1, Anton Berns |
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Allele Type | Targeted (Conditional ready (e.g. floxed), No functional change) |
Allele Synonym(s) | p53Co; p53F; p53F2-10; p53F2-10F; p53fl; p53flox; p53L; p53lox; p53LoxP; p53Fl; Tp53flx; Trp53f; Trp53F2-10; Trp53F2-F10; Trp53Fl; Trp53loxP |
Gene Symbol and Name | Trp53, transformation related protein 53 |
Gene Synonym(s) | |
Strain of Origin | 129P2/OlaHsd |
Chromosome | 11 |
Molecular Note | Insertion of loxP sites flanking exons 2 through 10. No effect on the normal function of the gene. |
Mutations Made By | Dr. Anton Berns, University of Amsterdam |
Allele Name | targeted mutation 4, Tyler Jacks |
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Allele Type | Targeted (Conditional ready (e.g. floxed), No functional change) |
Allele Synonym(s) | caKRas; KR; K-Ras(G12D)fl; KrasG12D; K-RasL; KrasLox; K-rasLSL; KrasLSL-G12D; Kras2tm4Tyj; Kras2tm14Tyj; K-RasG12D; Lox-Stop-Lox-KrasG12D; LSL-Kras G12D; LSL-K-ras G12D; LSL-KrasG12D; LSL-K-rasG12D; LSL-KrasG12D |
Gene Symbol and Name | Kras, Kirsten rat sarcoma viral oncogene homolog |
Gene Synonym(s) | |
Strain of Origin | 129S4/SvJae |
Chromosome | 6 |
Molecular Note | By homologous recombination in ES cells, the Kras2 locus was targeted with a cassette containing an oncogenic form of the KRAS2 protein in which the glycine at position 12 had been substituted with a an aspartic acid. A loxP flanked stop codon was included upstream of the inserted Kras2 sequence, such that the mutant transcript would be expressed only after cre-mediated recombination. |
Mutations Made By | Dr. Tyler Jacks, Massachusetts Institute of Technology |
Allele Name | transgene insertion, Douglas A Melton |
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Allele Type | Transgenic (Recombinase-expressing) |
Allele Synonym(s) | Pdx1-CreER |
Gene Symbol and Name | Tg(Pdx1-cre/Esr1*)#Dam, transgene insertion, Douglas A Melton |
Gene Synonym(s) | |
Promoter | Pdx1, pancreatic and duodenal homeobox 1, mouse, laboratory |
Expressed Gene | cre/Esr1, Cre recombinase and estrogen receptor 1 fusion gene, |
Site of Expression | Tamoxifen induction drives mosaic expression of cre recombinase in endocrine, exocrine, and duct tissue of the pancreas. |
Strain of Origin | (C57BL/6 x CBA)F1 |
Chromosome | UN |
Molecular Note | Sequence encoding a tamoxifen inducible form of a cre recombinase/estrogen receptor fusion protein was adjoined to the Ipf1 promoter to drive mosaic expression of cre recombinase in endocrine, exocrine, and duct tissue of the pancreas. The pound symbol (#) is used when no line is specified and/or lines are pooled. |
When maintaining a live colony, mice that are heterozygous for Krastm4Tyj [KrasLSL-G12D], homozygous for Trp53tm1Brn [p53LoxP] and homozygous for Tg(Pdx1-cre/Esr1*)#Dam [Pdx1-CreER] may be bred to mice that are heterozygous for KrasLSL-G12D or wildtype at the Kras locus, homozygous for p53LoxP and homozygous for Pdx1-CreER.
Mice homozygous for KrasLSL-G12D die in utero.
het, hom, hom 
When using the KPC, tamoxifen-inducible
mouse strain in a publication, please cite the originating article(s) and include JAX stock #032429 in your Materials and Methods section.
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