Overview

Also Known As:KPC:APC, KPC:APC

The inducible KPC:APC mouse model of KRAS mutated colorectal cancer combines the oncogenic conditional Kras^G12D allele, the conditional Apc^f allele and a tamoxifen inducible Cre recombinase (CDX2-Cre-ER^T2) with cre expression in adult epithelium of the distal intestinal tract. Mice develop malignant colonic tumors 25-30 days post tamoxifen induction.

Donating Investigator

Dr. Radhashree Maitra, Albert Einstein College of Medicine

Dr. Sanjay Goel, Albert Einstein College of Medicine

Genetic overview

Genetic Background	Generation
000664 C57BL/6J	?+pN1 (2020-10-12 00:00:00)

Kras^tm4Tyj

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

Tg(CDX2-cre/ERT2)752Erf

Allele Type
Transgenic (Recombinase-expressing, Inducible)

Apc^tm1Tno

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed), Hypomorph)	Apc	adenomatosis polyposis coli

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Research Applications

Cancer Research
Research Tools

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Base Price

Starting at:

$255.00 Domestic price for female

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Details

Detailed Description

KPC:APC is an inducible mouse model of KRAS mutated colorectal cancer. The model combines a floxed Kras^G12D allele that carries a point mutation (G12D) in; the Kirsten rat sarcoma viral oncogene homolog (Kras) gene whose expression is blocked by the presence of a loxP-flanked stop codon, an Apc (APC, WNT signaling pathway regulator) allele with floxed exon 14, and a tamoxifen inducible Cre recombinase (CDX2-Cre-ER^T2) with a human caudal type homeo box 2 (CDX2) promoter/enhancer sequence directing expression of CreER^T2 fusion gene (a Cre recombinase fused to a human estrogen receptor ligand binding domain). Restricted to the cytoplasm, Cre-ER^T2 can only gain access to the nuclear compartment after exposure to tamoxifen. Cre expression is directed to epithelium of the distal ileum and cecum, and throughout the colon from the crypt base to the luminal surface. Mice heterozygous for Kras, homozygous for Apc and hemizygous for CDX2-Cre-ER^T2 are viable and fertile. Please note that in the homozygous state Kras^tm4Tyj is embryonic lethal. The donating investigator reports that cre expression is leaky in 10% of mice. Following tamoxifen induction, KPC:APC mice develop malignant colonic tumors with within 25-30 days (tamoxifen dose .1 mg/20 g weight). Extensive inflammation with multiple small tumors is observed in the cecum, ascending and transverse colon, and large bowel. Histological and molecular analysis of tumors indicates that they resemble human colorectal carcinoma. Mice live an average of 165 days, dying of cachexia and rectal bleeding. Untreated mice live an average 2 years, 10% of untreated mice develop rectal prolapse around 165 days, subsequently dying of cachexia and rectal bleeding.

Development

For the Kras^tm4Tyj allele, a targeting vector was designed to place a G12D point mutation in exon 1 of the Kras gene on Chromosome 6 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. 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. The resulting chimeric animals were crossed to C57BL/6J and offspring were backcrossed to C57BL/6J for more than 10 generations.

For the Apc^tm1Tno allele (also known as Apc^fl or Apc^580S), the targeting construct contains a loxP site inserted into intron 13 and a PGK neomycin cassette followed by a second loxP site inserted in to intron 14 of the Apc gene on Chromosome 18. Cre-mediated recombination results in deletion of exon 14 rsulting in a frameshift silent mutation at codon 580. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to C57BL/6J and offspring were backcrossed to C57BL/6J for 20 generations.

The CDX2-CreER^T2 transgene was designed with a 9.5 kb promoter fragment from the 5' flanking sequences of human caudal type homeo box 2 (CDX2) gene, a creER^T2 fusion gene (a Cre recombinase fused to a human estrogen receptor ligand binding domain), and a bovine growth hormone polyadenylation cassette. This transgene was injected into (C57BL/6J x SJL/J) hybrid cells. Transgenic mice from founder line 752 were bred to C57BL/6J mice and offspring were crossed to C57BL/6J for at least 10 generations.

Mice homozygous for Apc^tm1Tno and hemizygous for Tg(CDX2-cre/ERT2)752Erf on the C57BL/6J genetic background were imported from Dr. Radhashree Maitra (Laboratory of Dr. Sanjay Goel, Albert Einstein College of Medicine) and combined with B6.129S4-Kras^tm4Tyj/J (Stock 008179) to establish the triple mutant KPC:APC colony.

Expression Data

Expressed Gene	cre/ERT2, Cre recombinase and estrogen receptor 1 (human) fusion gene,
Site of Expression	Upon tamoxifen administration, cre activity was detected in the distal ileal, cecal, colonic, and rectal epithelium.
Site of Expression

Control Suggestions

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Maitra R; Thavornwatanayong T; Venkatesh MK; Chandy C; Vachss D; Augustine T; Guzik H; Koba W; Liu Q; Goel S. 2019. Development and Characterization of a Genetic Mouse Model of KRAS Mutated Colorectal Cancer. Int J Mol Sci 20(22)PubMed: 31766149 MGI: J:289010

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Genetics

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)
Site of Expression	Cre-inducible expression of oncogenic Kras^G12D protein
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(CDX2-cre/ERT2)752Erf

Allele Symbol: Tg(CDX2-cre/ERT2)752Erf

Allele Name	transgene insertion 752, Eric Fearon
Allele Type	Transgenic (Recombinase-expressing, Inducible)
Allele Synonym(s)	CDX2-creERT2; CDX2P9.5-NLSCre
Gene Symbol and Name	Tg(CDX2-cre/ERT2)752Erf, transgene insertion 752, Eric Fearon
Gene Synonym(s)
Promoter	CDX2, caudal type homeobox 2, human
Expressed Gene	cre/ERT2, Cre recombinase and estrogen receptor 1 (human) fusion gene,
Site of Expression	Upon tamoxifen administration, cre activity was detected in the distal ileal, cecal, colonic, and rectal epithelium.
Strain of Origin	(C57BL/6J x SJL/J)
Chromosome	UN
Molecular Note	The transgene was designed with a 9.5 kb promoter fragment from the 5' flanking sequences of human caudal type homeo box 2 (CDX2) gene, a creERT2 fusion gene (a Cre recombinase fused to a human estrogen receptor ligand binding domain), and a bovine growth hormone polyadenylation cassette. This transgene was injected into (C57BL/6J x SJL/J) hybrid cells. Transgenic mice from founder line 752 were bred to C57BL/6J mice. The donating investigator reports that this strain was maintained by breeding hemizygous mice with C57BL/6J inbred mice for at least 4 generations.

Apc^tm1Tno

Allele Symbol: Apc^tm1Tno

Allele Name	targeted mutation 1, Tetsuo Noda
Allele Type	Targeted (Conditional ready (e.g. floxed), Hypomorph)
Allele Synonym(s)	580S; Apc^{580S flox}; Apc^580s; Apc^f; Apc^fl; Apc^loxP; Apc^lx
Gene Symbol and Name	Apc, adenomatosis polyposis coli
Gene Synonym(s)
Strain of Origin	129S4/SvJae
Chromosome	18
Molecular Note	One loxP site was inserted into intron 13 and the other, with a PGK-neo cassette, into intron 14. Northern blot analysis revealed that RNA expression in the intestinal tract of homozygous mutants was about 30% of that in wild-type mice. Protein expression in the colon of homozygotes by immunohistochemistry was indistinguishable from that of wild-type mice. Western blot analysis of lysates from mouse embryo fibroblasts showed reduced expression of the protein.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cancer Research
- Cre-lox System
  - Cre Recombinase expression: inducible
- Increased Tumor Incidence
  - Other Tissues/Organs: GI tract (stomach, intestine, colon)
Research Tools
- Cre-lox System
  - Cre Recombinase Expression: Inducible
  - Tamoxifen-inducible

Mammalian Phenotype Terms by Genotype

References

Maitra R; Thavornwatanayong T; Venkatesh MK; Chandy C; Vachss D; Augustine T; Guzik H; Koba W; Liu Q; Goel S. 2019. Development and Characterization of a Genetic Mouse Model of KRAS Mutated Colorectal Cancer. Int J Mol Sci 20(22)PubMed: 31766149 MGI: J:289010

Additional - Kras^tm4Tyj related

Additional - Apc^tm1Tno related

Additional - Tg(CDX2-cre/ERT2)752Erf related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Tg(CDX2-Cre/ERT2)752Erf alternate2
- QPCR:Generic Cre Quantitative PCR
- Standard PCR:Apc
- Genotyping resources and troubleshooting
Breeding Considerations

The strain is maintained as heterozygous for Kras^tm4Tyj, homozygous for Apc^tm1Tnoand hemizygous for Tg(CDX2-cre/ERT2)752Erf. In the homozygous state, Kras^tm4Tyj is embryonic lethal.
- Additional Breeding and Husbandry Support
Mating System
- Heterozygous for Kras^tm4Tyj homozygous for Apc^tm1Tno noncarrier for Tg(CDX2-cre/ERT2)752Erf x Wildtype for Kras^tm4Tyj homozygous for Apc^tm1Tno homozygous
- for Tg(CDX2-cre/ERT2)752Erf and reciprocal
Citation
When using the KPC:APC mouse strain in a publication, please cite the originating article(s) and include JAX stock #035169 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX18 (Maximum)

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:KPC:APC, KPC:APC

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

Selected References

Krastm4Tyj

Allele Symbol: Krastm4Tyj

Tg(CDX2-cre/ERT2)752Erf

Allele Symbol: Tg(CDX2-cre/ERT2)752Erf

Apctm1Tno

Allele Symbol: Apctm1Tno

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 - Apctm1Tno related

Additional - Tg(CDX2-cre/ERT2)752Erf related

Genotyping Protocols

Breeding Considerations

Mating System

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

Kras^tm4Tyj

Allele Symbol: Kras^tm4Tyj

Apc^tm1Tno

Allele Symbol: Apc^tm1Tno

Additional - Kras^tm4Tyj related

Additional - Apc^tm1Tno related