Overview

Also Known As:KPC, tamoxifen-inducible

This tamoxifen-inducible KPC strain may be used as a model for pancreatic ductal adenocarcinoma (PDAC).

Donating Investigator

The Jackson Laboratory

Genetic overview

Genetic Background	Generation
	N1F4 (2020-02-27 00:00:00)

Trp53^tm1Brn

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed), No functional change)	Trp53	transformation related protein 53

Kras^tm4Tyj

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed), No functional change)	Kras	Kirsten rat sarcoma viral oncogene homolog

Allele Type
Transgenic (Recombinase-expressing)

Research Applications

Research Tools
Cancer Research

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Base Price

Starting at:

$255.00 Domestic price for female 4-week

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Details

Detailed Description

This KPC strain is a tamoxifen-inducible model for pancreatic ductal adenocarcinoma (PDAC) carrying the Kras LSL G12D (Kras^tm4Tyj) allele, the Trp53^tm1Brn 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 Kras^tm4Tyj allele [Kras^LSL-G12D] contains a point mutation (G12D) whose expression is blocked by the presence of a loxP-flanked stop codon. Mice homozygous for this Kras^tm4Tyj allele die in utero. Cre-mediated recombination can excise the stop codon and permit the oncogenic protein to be expressed.

The Trp53^tm1Brn allele [p53^LoxP] contains loxP sites flanking exons 2 through 10 of the transformation related protein 53 gene. Mice homozygous for the Trp53^tm1Brn 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-ER^TM; 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.

Development

This Kras^LSL-G12D;p53^LoxP;Pdx1-CreER triple mutant line was generated by crossing three single mutant strains:
B6.129S4-Kras^tm4Tyj/J Stock No. 008179,
B6.129P2-Trp53^tm1Brn/J Stock No. 008462,
STOCK Tg(Pdx1-cre/Esr1*)#Dam/J Stock No. 024968.

For the Kras^tm4Tyj allele [Kras^LSL-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 Trp53^tm1Brn mutation [p53^LoxP or p53^flox], 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-ER^TM 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.

Expression Data

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.

Control Suggestions

Approximate Controls

None Available (Mice from the colony that are heterozygous for the targeted mutations and noncarrier for the transgene should be considered for use as controls. The most appropriate control animal will depend on the nature of the experiment. )

Additional Information

Considerations for Choosing Controls

Selected References

Maddipati R; Stanger BZ. 2015. Pancreatic Cancer Metastases Harbor Evidence of Polyclonality. Cancer Discov 5(10):1086-97PubMed: 26209539 MGI: J:230607

View All References

Genetics

Trp53^tm1Brn

Allele Symbol: Trp53^tm1Brn

Allele Name	targeted mutation 1, Anton Berns
Allele Type	Targeted (Conditional ready (e.g. floxed), No functional change)
Allele Synonym(s)	p53^Co; p53^F; p53^F2-10; p53^F2-10F; p53^fl; p53^flox; p53^L; p53^lox; p53^LoxP; p53Fl; Tp53^flx; Trp53^f; Trp53^F2-10; Trp53^F2-F10; Trp53^Fl; Trp53^loxP
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

Kras^tm4Tyj

Allele Symbol: Kras^tm4Tyj

Allele Name	targeted mutation 4, Tyler Jacks
Allele Type	Targeted (Conditional ready (e.g. floxed), No functional change)
Allele Synonym(s)	caKRas; KR; K-Ras(G12D)^fl; Kras^G12D; K-Ras^L; Kras^Lox; K-ras^LSL; Kras^LSL-G12D; Kras2^tm4Tyj; Kras2tm14Tyj; K-RasG12D; Lox-Stop-Lox-Kras^G12D; LSL-Kras G12D; LSL-K-ras G12D; LSL-Kras^G12D; LSL-K-ras^G12D; 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

Tg(Pdx1-cre/Esr1*)#Dam

Allele Symbol: Tg(Pdx1-cre/Esr1*)#Dam

Allele Name	transgene insertion, Douglas A Melton
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.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Research Tools
- Cancer Research
  - Cre-lox System
- Cre-lox System
  - Cre Recombinase Expression: Inducible
Cancer Research
- Cre-lox System
  - Cre Recombinase expression: inducible
- Other

Mammalian Phenotype Terms by Genotype

References

Maddipati R; Stanger BZ. 2015. Pancreatic Cancer Metastases Harbor Evidence of Polyclonality. Cancer Discov 5(10):1086-97PubMed: 26209539 MGI: J:230607

Additional - Kras^tm4Tyj related

Additional - Trp53^tm1Brn related

Additional - Tg(Pdx1-cre/Esr1*)#Dam related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Probe:Generic Cre Probe
- QPCR:Generic Cre Quantitative PCR
- Probe:Trp53 Probe
- Standard PCR:Generic Cre
- Standard PCR:Trp53
- Standard PCR:Tg(Pdx1-cre/Esr1*)#Dam
- Standard PCR:Generic Cre Melt Curve Analysis
- Standard PCR:Kras Alt1
- QPCR:Tg(Pdx1-cre/Esr1*)#Dam qPCR Alt 1
- Genotyping resources and troubleshooting
Dietary Information
- New Diet as of March 2015: Lab Diet® 5K0Q (6% fat)
Breeding Considerations

When maintaining a live colony, mice that are heterozygous for Kras^tm4Tyj [Kras^LSL-G12D], homozygous for Trp53^tm1Brn [p53^LoxP] and homozygous for Tg(Pdx1-cre/Esr1*)#Dam [Pdx1-CreER] may be bred to mice that are heterozygous for Kras^LSL-G12D or wildtype at the Kras locus, homozygous for p53^LoxP and homozygous for Pdx1-CreER.
Mice homozygous for Kras^LSL-G12D die in utero.
- Additional Breeding and Husbandry Support
Mating System
- het, hom, hom
- x WT, hom, hom and recip.
Appearance
- Black or Albino
Citation
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.

Animal Health Reports

Facility Barrier Level Descriptions

AX10 (Standard)

Pricing & Availability

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Also Known As:KPC, tamoxifen-inducible

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

Selected References

Trp53tm1Brn

Allele Symbol: Trp53tm1Brn

Krastm4Tyj

Allele Symbol: Krastm4Tyj

Tg(Pdx1-cre/Esr1*)#Dam

Allele Symbol: Tg(Pdx1-cre/Esr1*)#Dam

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

References

Additional - Krastm4Tyj related

Additional - Trp53tm1Brn related

Additional - Tg(Pdx1-cre/Esr1*)#Dam related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Appearance

Citation

Animal Health Reports

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Trp53^tm1Brn

Allele Symbol: Trp53^tm1Brn

Kras^tm4Tyj

Allele Symbol: Kras^tm4Tyj

Additional - Kras^tm4Tyj related

Additional - Trp53^tm1Brn related