Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse   Donating Investigator Dr. Tyler Jacks,   Massachusetts Institute of Technology

Description
These targeted mutant mice carry a R270H missense mutation in exon 8 of the gene. Heterozygous mice develop a broad spectrum of tumors with a mean survival time of 16 months. Prominent tumor types include osteosarcomas (often metastatic), hemangiosarcomas, B-cell lymphomas and a variety of carcinomas. Homozygous mice also develop an array of tumor types including a variety of hematological tumors (particularly T-cell lymphomas), hemangiosarcomas, soft-tissue sarcomas, ostersarcomas, primitive tumors (particularly male teratocarcinomas), and a variety of epithelial carcinomas. Homozygotes have a mean survival time of 4.5 months. Mutant protein is expressed in all of the places that wildtype protein is expressed in normal tissues. Irradiation or DNA damage leads to substantially increased protein levels. Expression is also upregulated in some tumor types. This strain may be useful in studies of cancer and Li-Fraumeni Syndrome.

Development
A targeting vector was designed to place a loxP-flanked stop cassette in intron 1 and an R270H missense mutation into exon 8. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Resultant mice were crossed with a protamine promoter-driven Cre strain to remove the stop cassette. The strain was backcrossed to a C57BL/6 background approximately ten times by the donating laboratory.

Related Strains

Strains carrying other alleles of Trp53

004301	129-Trp53tm1Holl/J
002080	129-Trp53tm1Tyj/J
008652	129S-Trp53tm2Tyj/J
008651	129S-Trp53tm3Tyj/J
008462	B6.129P2-Trp53tm1Brn/J
002101	B6.129S2-Trp53tm1Tyj/J
008183	B6.129S4(Cg)-Trp53tm2.1Tyj/J
007218	B6.129S6-Trp53tm2Xu/J
011109	B6.Cg-Trp53tm2Glo/Kvm
007962	B6.FVB-Tg(MMTV-neu/OT-I/OT-II)CBnel Tg(Trp53R172H)8512Jmr/J
017767	B6;129-Trp53tm1.1Dgk/J
008045	B6;129-Trp53tm2Holl/J
006980	B6;129-Trp53tm2Xu/J
008191	B6;129S2-Trp53tm1Tyj Nf1tm1Tyj/J
002103	B6;129S2-Trp53tm1Tyj/J
008181	B6;129S4-Trp53tm4Tyj/J
008361	B6;129S4-Trp53tm5Tyj/J
002526	C.129S2(B6)-Trp53tm1Tyj/J
002547	C3Ou.129S2(B6)-Trp53tm1Tyj/J
002899	FVB.129S2(B6)-Trp53tm1Tyj/J
002659	FVB/N-Tg(Trp53R172H)8512Jmr/J
002660	FVB/N-Tg(Trp53R172L)4491Jmr/J
017530	STOCK Iis2tm2(ACTB-tdTomato,-EGFP)Luo Trp53tm1Tyj Nf1tm1Par/J
012620	STOCK Trp53tm1Brd Brca1tm1Aash Tg(LGB-cre)74Acl/J
003262	STOCK Tg(Trp53A135V)L3Ber/J

View Strains carrying other alleles of Trp53     (25 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Li-Fraumeni Syndrome 1; LFS1

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Adrenocortical Carcinoma, Hereditary; ADCC   (TP53) Basal Cell Carcinoma, Susceptibility to, 7; BCC7   (TP53) Breast Cancer   (TP53) Colorectal Cancer; CRC   (TP53) Glioma Susceptibility 1; GLM1   (TP53) Hepatocellular Carcinoma   (TP53) Nasopharyngeal Carcinoma   (TP53) Osteogenic Sarcoma   (TP53) Pancreatic Cancer   (TP53) Papilloma of Choroid Plexus   (TP53)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Trp53^tm3.1Tyj/Trp53⁺

        involves: 129S4/SvJae

• mortality/aging
• premature death
  • mean life span is 15.8 months   (MGI Ref ID J:95316)
• tumorigenesis
• increased metastatic potential
  • compared to Trp53^tm1Tyj   (MGI Ref ID J:95316)
• increased tumor incidence   (MGI Ref ID J:95316)
• • B cell derived lymphoma
    • 5 of 36 develop B cell lymphomas generally arising in the spleen or mesenteric lymph nodes   (MGI Ref ID J:95316)
  • carcinoma
    • the incidence of carcinomas is increased compared to Trp53^tm1Tyj heterozygotes   (MGI Ref ID J:95316)
    • 5 of 36 develop squamous cell carcinomas and a single case each of transitional cell renal carcinoma and intestinal carcinoma are seen   (MGI Ref ID J:95316)
  • • hepatocellular carcinoma
      • 2 of 36 develop hepatocellular carcinomas   (MGI Ref ID J:95316)
    • lung adenocarcinoma
      • 7 of 36 develop lung adenocarcinomas, several with malignant features commonly seen in human lung adenocarcinoma including nuclear atypia (5 of 7), desmoplasia (4 of 7), and metaplasias (2 of 7)   (MGI Ref ID J:95316)
    • squamous cell carcinoma
      • 5 of 36 develop squamous cell carcinomas   (MGI Ref ID J:95316)
• cellular phenotype
• decreased cellular sensitivity to gamma-irradiation
  • resistance to gamma-irradiation induced apoptosis is increased compared to Trp53^tm1Tyj hterozygotes   (MGI Ref ID J:95316)
• increased cell proliferation
  • a larger fraction of MEFs are in S phase compared to Trp53^tm1Tyj hterozygotes; however DNA damage-induced G1 arrest is intact   (MGI Ref ID J:95316)

Trp53^tm3.1Tyj/Trp53⁺

        involves: 129S4/SvJae * SKH1

• tumorigenesis
• increased skin tumor incidence
  • whether spontaneous or induced, mice develop epithelial, proliferative lesions forming a continuum from nonneoplastic squamous keratosis and acanthosis to squamous cell papillomas, actinic keratosis and keratoacanthoma with increasing degrees of atypia and dysplasia, carcinoma in situ, up to invasive squamous cell carcinoma   (MGI Ref ID J:121734)
• mammary adenocarcinoma
  • in 2 mice   (MGI Ref ID J:121734)
• integument phenotype
• increased skin tumor incidence
  • whether spontaneous or induced, mice develop epithelial, proliferative lesions forming a continuum from nonneoplastic squamous keratosis and acanthosis to squamous cell papillomas, actinic keratosis and keratoacanthoma with increasing degrees of atypia and dysplasia, carcinoma in situ, up to invasive squamous cell carcinoma   (MGI Ref ID J:121734)

View Research Applications

Research Applications

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

Cancer Research
Increased Tumor Incidence
      Lymphomas
      Lymphomas: B cell lymphomas

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Trp53tm3.1Tyj
Allele Name		targeted mutation 3.1, Tyler Jacks
Allele Type		Targeted (knock-in)
Common Name(s)		Trp53R270H; p53 R270H; p53H; p53R270H;
Mutation Made By		Dr. Tyler Jacks,   Massachusetts Institute of Technology
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Promoter		Trp53, transformation related protein 53, mouse, laboratory
Molecular Note		The loxP flanked stop cassette was removed from Trp53tm3Tyj via cre-mediated recombination, leaving an R270H missense mutation in exon 8. Quantitative real-time PCR confirmed that the point mutation allele was expressed at a level comparable to wild-type. [MGI Ref ID J:95316]

Genotyping

Genotyping Information

Genotyping Protocols

Trp53^tm3.1Tyj, Pyrosequencing

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Olive KP; Tuveson DA; Ruhe ZC; Yin B; Willis NA; Bronson RT; Crowley D; Jacks T. 2004. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119(6):847-60. [PubMed: 15607980]  [MGI Ref ID J:95316]

Additional References

Trp53^tm3.1Tyj related

Bertout JA; Patel SA; Fryer BH; Durham AC; Covello KL; Olive KP; Goldschmidt MH; Simon MC. 2009. Heterozygosity for hypoxia inducible factor 1alpha decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res 69(7):3213-20. [PubMed: 19293180]  [MGI Ref ID J:147359]

Kirsch DG; Dinulescu DM; Miller JB; Grimm J; Santiago PM; Young NP; Nielsen GP; Quade BJ; Chaber CJ; Schultz CP; Takeuchi O; Bronson RT; Crowley D; Korsmeyer SJ; Yoon SS; Hornicek FJ; Weissleder R; Jacks T. 2007. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med 13(8):992-7. [PubMed: 17676052]  [MGI Ref ID J:125101]

Morton JP; Timpson P; Karim SA; Ridgway RA; Athineos D; Doyle B; Jamieson NB; Oien KA; Lowy AM; Brunton VG; Frame MC; Evans TR; Sansom OJ. 2010. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci U S A 107(1):246-51. [PubMed: 20018721]  [MGI Ref ID J:156461]

Su X; Chakravarti D; Flores ER. 2013. p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer 13(2):136-43. [PubMed: 23344544]  [MGI Ref ID J:193489]

Tian H; Callahan CA; DuPree KJ; Darbonne WC; Ahn CP; Scales SJ; de Sauvage FJ. 2009. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A 106(11):4254-9. [PubMed: 19246386]  [MGI Ref ID J:146777]

Vinall RL; Chen JQ; Hubbard NE; Sulaimon SS; Shen MM; Devere White RW; Borowsky AD. 2012. Initiation of prostate cancer in mice by Tp53R270H: evidence for an alternative molecular progression. Dis Model Mech 5(6):914-20. [PubMed: 22563073]  [MGI Ref ID J:191153]

Wijnhoven SW; Speksnijder EN; Liu X; Zwart E; vanOostrom CT; Beems RB; Hoogervorst EM; Schaap MM; Attardi LD; Jacks T; van Steeg H; Jonkers J; de Vries A. 2007. Dominant-negative but not gain-of-function effects of a p53.R270H mutation in mouse epithelium tissue after DNA damage. Cancer Res 67(10):4648-56. [PubMed: 17510390]  [MGI Ref ID J:121734]

Wijnhoven SW; Zwart E; Speksnijder EN; Beems RB; Olive KP; Tuveson DA; Jonkers J; Schaap MM; van den Berg J; Jacks T; van Steeg H; de Vries A. 2005. Mice expressing a mammary gland-specific R270H mutation in the p53 tumor suppressor gene mimic human breast cancer development. Cancer Res 65(18):8166-73. [PubMed: 16166291]  [MGI Ref ID J:101617]

Wu R; Baker SJ; Hu TC; Norman KM; Fearon ER; Cho KR. 2013. Type I to type II ovarian carcinoma progression: mutant Trp53 or Pik3ca confers a more aggressive tumor phenotype in a mouse model of ovarian cancer. Am J Pathol 182(4):1391-9. [PubMed: 23499052]  [MGI Ref ID J:195346]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	When maintained as a live colony, heterozygotes may be bred. Homozygotes can breed, but have a shortened lifespan (~4.5 months).

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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.

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