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

Former Names 129S4-Krastm3Tyj/J    (Changed: 02-APR-08 ) Type Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator Dr. Tyler Jacks,   Massachusetts Institute of Technology

Description
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.

Development
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-ras^LA2 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.

Related Strains

Strains carrying other alleles of Kras

002674	129-Krastm1Tyj/J
008180	129S/Sv-Krastm4Tyj/J
008179	B6.129S4-Krastm4Tyj/J
008653	B6;129-Krastm5Tyj/J

View Strains carrying other alleles of Kras     (4 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).

Lung Cancer

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Bladder Cancer   (KRAS) Breast Cancer   (KRAS) Cardiofaciocutaneous Syndrome   (KRAS) Gastric Cancer, Hereditary Diffuse; HDGC   (KRAS) Noonan Syndrome 3; NS3   (KRAS) Pancreatic Cancer   (KRAS) Schimmelpenning-Feuerstein-Mims Syndrome; SFM   (KRAS)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Kras^tm3Tyj/Kras⁺

        involves: 129S2/SvPas

• mortality/aging
• premature death
  • mean age at death is ~250 days on pure 129/Sv background compared to 200 days on mixed background   (MGI Ref ID J:68981)
• tumorigenesis
• T cell derived lymphoma
  • ~30% of animals develop thymic lymphoma; incidence is higher than on pure 129/Sv background   (MGI Ref ID J:68981)
• increased lung tumor incidence
  • 100% of mice examined at 3-4 months of age have developed lung tumors   (MGI Ref ID J:119477)
• skin papilloma
  • about 40% of mice develop skin papillomas, with slightly higher incidence than on mixed 129 and C57BL/6 background   (MGI Ref ID J:68981)
• integument phenotype
• skin papilloma
  • about 40% of mice develop skin papillomas, with slightly higher incidence than on mixed 129 and C57BL/6 background   (MGI Ref ID J:68981)

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

Kras^tm3Tyj/Kras⁺

        involves: 129S2/SvPas * C57BL/6

• mortality/aging
• premature death
  • mean age at death is ~200 days   (MGI Ref ID J:68981)
• tumorigenesis
• increased tumor incidence
  • all animals at time of death/sacrifice have extensive tumor burden   (MGI Ref ID J:68981)
  • mice display a more rapid tumor phenotype than Kras^tm2Tyj heterozygotes   (MGI Ref ID J:68981)
• • T cell derived lymphoma
    • animals are prone to thymic lymphomas (seen in ~40% of animals)   (MGI Ref ID J:68981)
  • increased lung tumor incidence
    • 100% of animals show multifocal tumors at time of death/sacrifice   (MGI Ref ID J:68981)
    • tumors are detectable at 1 week of age as small pleural nodules; multiplicity and size of tumors increases with age, and ultimately result in respiratory distress and death   (MGI Ref ID J:68981)
    • tumors range from mild hyperplasia/dysplasia to overt carcinoma; small lesions consist of hyperplastic alveolar epithelium   (MGI Ref ID J:68981)
    • in older mice, infrequent metastases to thoracic lymph nodes, the kidney and other visceral organs   (MGI Ref ID J:68981)
  • • increased lung adenoma incidence
      • as lesions enlarge, they form small alveolar adenomas; some show areas of glandular differentiation   (MGI Ref ID J:68981)
    • lung adenocarcinoma
      • 5-10% of tumors have features of well-differentiated human papillary adenocarcinoma   (MGI Ref ID J:68981)
  • skin papilloma
    • animals are prone to skin papillomas (seen in ~20% of animals); tumors typically arising on ears and snout are predominantly pedunculated and show limited tendency to progress to squamous cell carcinoma   (MGI Ref ID J:68981)
• digestive/alimentary phenotype
• abnormal large intestine crypts of Lieberkuhn morphology
  • mutants have multiple aberrant crypt foci (ACF) of the colon   (MGI Ref ID J:68981)
• endocrine/exocrine gland phenotype
• abnormal large intestine crypts of Lieberkuhn morphology
  • mutants have multiple aberrant crypt foci (ACF) of the colon   (MGI Ref ID J:68981)
• integument phenotype
• skin papilloma
  • animals are prone to skin papillomas (seen in ~20% of animals); tumors typically arising on ears and snout are predominantly pedunculated and show limited tendency to progress to squamous cell carcinoma   (MGI Ref ID J:68981)

View Research Applications

Research Applications

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

Cancer Research
Increased Tumor Incidence
      Lymphomas
      Lymphomas: thymic
      Other Tissues/Organs
      Other Tissues/Organs: lung
      Skin Cancers
Oncogenes

Developmental Biology Research
Embryonic Lethality (Homozygous)

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Krastm3Tyj
Allele Name		targeted mutation 3, Tyler Jacks
Allele Type		Targeted (knock-in)
Common Name(s)		K-rasLA2; KrasG12D; KrasLA2-G12D; KrasLA2;
Mutation Made By		Dr. Tyler Jacks,   Massachusetts Institute of Technology
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Promoter		Kras, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, mouse, laboratory
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). [MGI Ref ID J:68981]

Genotyping

Genotyping Information

Genotyping Protocols

Kras^tm3Tyj, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Johnson L; Mercer K; Greenbaum D; Bronson RT; Crowley D; Tuveson DA; Jacks T. 2001. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410(6832):1111-6. [PubMed: 11323676]  [MGI Ref ID J:68981]

Additional References

Kras^tm3Tyj related

Calcagno SR; Li S; Colon M; Kreinest PA; Thompson EA; Fields AP; Murray NR. 2008. Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon. Int J Cancer 122(11):2462-70. [PubMed: 18271008]  [MGI Ref ID J:135568]

Dovey JS; Zacharek SJ; Kim CF; Lees JA. 2008. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc Natl Acad Sci U S A 105(33):11857-62. [PubMed: 18697930]  [MGI Ref ID J:139699]

Feldser DM; Kostova KK; Winslow MM; Taylor SE; Cashman C; Whittaker CA; Sanchez-Rivera FJ; Resnick R; Bronson R; Hemann MT; Jacks T. 2010. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468(7323):572-5. [PubMed: 21107428]  [MGI Ref ID J:166972]

Granville CA; Memmott RM; Balogh A; Mariotti J; Kawabata S; Han W; Lopiccolo J; Foley J; Liewehr DJ; Steinberg SM; Fowler DH; Hollander MC; Dennis PA. 2009. A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS ONE 4(3):e5061. [PubMed: 19330036]  [MGI Ref ID J:147455]

Gupta S; Ramjaun AR; Haiko P; Wang Y; Warne PH; Nicke B; Nye E; Stamp G; Alitalo K; Downward J. 2007. Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129(5):957-68. [PubMed: 17540175]  [MGI Ref ID J:122866]

Hatley ME; Patrick DM; Garcia MR; Richardson JA; Bassel-Duby R; van Rooij E; Olson EN. 2010. Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18(3):282-93. [PubMed: 20832755]  [MGI Ref ID J:164198]

Hegedus B; Banerjee D; Yeh TH; Rothermich S; Perry A; Rubin JB; Garbow JR; Gutmann DH. 2008. Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma. Cancer Res 68(5):1520-8. [PubMed: 18316617]  [MGI Ref ID J:132860]

Hollander MC; Maier CR; Hobbs EA; Ashmore AR; Linnoila RI; Dennis PA. 2011. Akt1 deletion prevents lung tumorigenesis by mutant K-ras. Oncogene 30(15):1812-21. [PubMed: 21242979]  [MGI Ref ID J:170765]

Hollander MC; Zhou X; Maier CR; Patterson AD; Ding X; Dennis PA. 2011. A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice. Carcinogenesis 32(8):1279-84. [PubMed: 21625009]  [MGI Ref ID J:174977]

Jang JW; Boxer RB; Chodosh LA. 2006. Isoform-specific ras activation and oncogene dependence during MYC- and Wnt-induced mammary tumorigenesis. Mol Cell Biol 26(21):8109-21. [PubMed: 16908535]  [MGI Ref ID J:114642]

Ling J; Kang Y; Zhao R; Xia Q; Lee DF; Chang Z; Li J; Peng B; Fleming JB; Wang H; Liu J; Lemischka IR; Hung MC; Chiao PJ. 2012. Kras(G12D)-Induced IKK2/beta/NF-kappaB Activation by IL-1alpha and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma. Cancer Cell 21(1):105-20. [PubMed: 22264792]  [MGI Ref ID J:180278]

Loeb KR; Kostner H; Firpo E; Norwood T; D Tsuchiya K; Clurman BE; Roberts JM. 2005. A mouse model for cyclin E-dependent genetic instability and tumorigenesis. Cancer Cell 8(1):35-47. [PubMed: 16023597]  [MGI Ref ID J:99695]

Macias-Perez I; Borza C; Chen X; Yan X; Ibanez R; Mernaugh G; Matrisian LM; Zent R; Pozzi A. 2008. Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer. Cancer Res 68(15):6127-35. [PubMed: 18676835]  [MGI Ref ID J:140034]

Mallakin A; Sugiyama T; Taneja P; Matise LA; Frazier DP; Choudhary M; Hawkins GA; D'Agostino RB Jr; Willingham MC; Inoue K. 2007. Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer. Cancer Cell 12(4):381-94. [PubMed: 17936562]  [MGI Ref ID J:126002]

Meylan E; Dooley AL; Feldser DM; Shen L; Turk E; Ouyang C; Jacks T. 2009. Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature 462(7269):104-7. [PubMed: 19847165]  [MGI Ref ID J:154041]

Murray NR; Jamieson L; Yu W; Zhang J; Gokmen-Polar Y; Sier D; Anastasiadis P; Gatalica Z; Thompson EA; Fields AP. 2004. Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo. J Cell Biol 164(6):797-802. [PubMed: 15024028]  [MGI Ref ID J:89285]

Pandey J; Umphress SM; Kang Y; Angdisen J; Naumova A; Mercer KL; Jacks T; Jakowlew SB. 2007. Modulation of tumor induction and progression of oncogenic K-ras-positive tumors in the presence of TGF- 1 haploinsufficiency. Carcinogenesis 28(12):2589-96. [PubMed: 17690114]  [MGI Ref ID J:127727]

Regala RP; Justilien V; Walsh MP; Weems C; Khoor A; Murray NR; Fields AP. 2011. Matrix metalloproteinase-10 promotes Kras-mediated bronchio-alveolar stem cell expansion and lung cancer formation. PLoS One 6(10):e26439. [PubMed: 22022614]  [MGI Ref ID J:179772]

Sangodkar J; Dhawan NS; Melville H; Singh VJ; Yuan E; Rana H; Izadmehr S; Farrington C; Mazhar S; Katz S; Albano T; Arnovitz P; Okrent R; Ohlmeyer M; Galsky M; Burstein D; Zhang D; Politi K; Difeo A; Narla G. 2012. Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response. J Clin Invest 122(7):2637-51. [PubMed: 22653055]  [MGI Ref ID J:190477]

Shaw AT; Meissner A; Dowdle JA; Crowley D; Magendantz M; Ouyang C; Parisi T; Rajagopal J; Blank LJ; Bronson RT; Stone JR; Tuveson DA; Jaenisch R; Jacks T. 2007. Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis. Genes Dev 21(6):694-707. [PubMed: 17369402]  [MGI Ref ID J:119477]

Sweet-Cordero A; Tseng GC; You H; Douglass M; Huey B; Albertson D; Jacks T. 2006. Comparison of gene expression and DNA copy number changes in a murine model of lung cancer. Genes Chromosomes Cancer 45(4):338-48. [PubMed: 16323170]  [MGI Ref ID J:105735]

Takahashi H; Ogata H; Nishigaki R; Broide DH; Karin M. 2010. Tobacco Smoke Promotes Lung Tumorigenesis by Triggering IKKbeta- and JNK1-Dependent Inflammation. Cancer Cell 17(1):89-97. [PubMed: 20129250]  [MGI Ref ID J:156928]

To MD; Perez-Losada J; Mao JH; Hsu J; Jacks T; Balmain A. 2006. A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat Genet 38(8):926-30. [PubMed: 16823377]  [MGI Ref ID J:111642]

Walter G; Ruediger R. 2012. Mouse model for probing tumor suppressor activity of protein phosphatase 2A in diverse signaling pathways. Cell Cycle 11(3):451-9. [PubMed: 22262169]  [MGI Ref ID J:182425]

Yin X; Cong X; Yan M; Zhang DE. 2009. Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice. Lung Cancer 63(2):194-200. [PubMed: 18571763]  [MGI Ref ID J:155787]

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 for a period of 4-6 months. Homozygotes are embryonic lethal.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

The Jackson Laboratory's Genotype Promise

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.

---

Ordering Information
JAX^® Mice
Surgical and Preconditioning Services
JAX^® Services
Customer Services and Support
Tel: 1-800-422-6423 or 1-207-288-5845
Fax: 1-207-288-6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries regarding Terms of Use

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCTS" means biological materials supplied by JACKSON, and their derivatives. "RECIPIENT" means each recipient of MICE, PRODUCTS, or services provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE or PRODUCTS from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON's prior written authorization.

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of mice, products or services, JACKSON will, at its option, provide credit or replacement for the mice or product received or the services provided.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS or services from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE and PRODUCTS are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or services. In addition, special terms and conditions of sale of certain MICE, PRODUCTS or services may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and services by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or services by JACKSON.