|These Braf knock-in mice carry a genetically modified allele of human BRaf, BRafCA, which expresses normal BRaf prior to Cre-mediated recombination, but after which BRafVE is expressed. These mice may be useful in studies of human malignancies, as well as for studying the RAS-activated RAF/MEK/ERK mitogen-activated protein kinase signaling pathway and pleiotropic regulators of the aberrant cancer cell physiology.|
Type Congenic; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote (Female x Male) 08-APR-13 Species laboratory mouse Generation F?+F11 (08-MAY-15)
Donating Investigator IMR Colony, The Jackson Laboratory
Mice homozygous for the Cre-activated BRaf mutant allele (BRafCA) are viable and fertile. Mice express the transcript encoded by endogenous exons 1-14 and loxP-flanked human exons 15-18 (BRafCA) prior to Cre recombinase exposure. Homozygous mice have "normal" BRaf expression, and no abnormalities are reported for homozygous BRafCA mice. Following Cre-mediated excision of the floxed sequences (human BRAF exons 15-18 and polyA signal), the transcripts are subsequently generated using the downstream mutant exon 15 (modified with a V600E amino acid substitution associated with constitutively active BRAFV600E in human cancers) and the endogenous downstream exons 16-18. The resulting BRafVE transcripts are subject to normal patterns of alternate splicing and differential exon usage, and BRafVE expression is observed at physiological levels. To discriminate the expression of the various BRaf mRNAs in heterozygous mice, silent restriction enzyme polymorphisms were incorporated into the exon 15 sequences of BRafCA (BamHI) and BRafVE (XbaI).
For example, when crossed to a strain expressing tamoxifen-inducible Cre recombinase (see Stock No. 017585), this mutant mouse strain may be useful in studies of lung tumors.
The BRafCA mutant mice were created by Dr. Martin McMahon (University of California, San Francisco). The BRafCA targeted mutation was designed to replace the endogenous Braf exon 15 with (from 5' to 3') a loxP site, the cDNA sequence encoded by human BRAF exons 15-18 (with a silent BamHI restriction site polymorphism in exon 15), the mouse Braf polyA sequences, a PGK-neo cassette (with triple transcriptional stop and SV40 polyA signal), a second loxP site, and a mouse exon 15 sequence modified via site-directed mutagenesis to harbor both a V600E amino acid substitution (associated with the constitutively active BRAFV600E mutation in human cancers) and also a silent XbaI restriction site polymorphism. The targeting vector was microinjected into 129Sv/OLA embryonic stem (ES) cells, and correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric mice were bred with FVB/N mice to establish the colony. BRafCA mutant mice were subsequently maintained on a C57BL/6 congenic background.
|Considerations for Choosing Controls|
Strains carrying Braftm1Mmcm alleleView Strains carrying Braftm1Mmcm (1 strain)Strains carrying other alleles of Braf
006373 129-Braftm1Sva/JView Strains carrying other alleles of Braf (1 strain)
View Related Disease (OMIM) TermsRelated Disease (OMIM) Terms provided by MGIView Mammalian Phenotype TermsMammalian Phenotype Terms provided by MGIassigned by genotype
The following phenotype information is associated with a similar, but not exact match to this JAX® Mice strain.
Braftm1Mmcm/Braf+involves: 129P2/OlaHsd (conditional)
- premature death
- 7-8 weeks after adenoviral Cre intranasal administration to 6- to 8-week old mutants, treated animals are euthanized because they show labored breathing and general wasting (MGI Ref ID J:121715)
- increased lung tumor incidence
- cellular origins of cancerous are ambiguous aslesions are Clara Cell antigen-negative, but majority of cells express Surfactant protein C as early as 2 weeks after Cre treatment (CCA and SP-C are both markers of alveolar type II pneumocytes) (MGI Ref ID J:121715)
- 4 weeks after Cre treatment, mice are treated for 28 days with a pharmacological inhibitor of MEK1/2 which prevents almost all tumor development, while vehicle-treated animals show numerous lung tumors (MGI Ref ID J:121715)
- increased lung adenocarcinoma incidence
- only 2 mice (of 57) that develop adenomas show evidence of progression to adenocarcinoma; cells from these mice display nuclear enlargement, hyperchromasia, and contour irregularities (MGI Ref ID J:121715)
- increased lung adenoma incidence
- 7 weeks after high dose Cre treatment, evidence of multiple adenomatous tumor formation is present in mouse lungs, while no tumors are detected in untreated mice after 6 months (MGI Ref ID J:121715)
- papillary adenomas are detected 6-8 weeks after lower dose adenoviral Cre treatment; lesions seem to increase in size and number (MGI Ref ID J:121715)
- lesions arise in alveolar ducts expanding outward and around broncioles (MGI Ref ID J:121715)
- at ~14 weeks, papillary adenomas undergo changes at periphery; cells change such that they have more cytoplasm and become eosinophilic (MGI Ref ID J:121715)
- after lower dose Cre treatement, adenomas do not grow beyond ~900 um in diameter (MGI Ref ID J:121715)
- respiratory system phenotype
- lung epithelium hyperplasia
- normal phenotype
- no abnormal phenotype detected
- mice are fertile and born at Mendelian ratios, but no further phenotypic analysis is provided (MGI Ref ID J:121715)
The following phenotype relates to a compound genotype created using this strain.
Contact JAX® Services email@example.com for customized breeding options.
Braftm1Mmcm/Braf+ Polr2atm1(cre/ERT2)Bbd/Polr2a+involves: 129P2/OlaHsd * C57BL/6 * SJL (conditional)
- increased lung adenoma incidence
- with induction of Cre expression from the transgene, multiple adenomatous tumors form in mouse lungs (MGI Ref ID J:121715)View Research ApplicationsResearch ApplicationsThis mouse can be used to support research in many areas including:
Cell Biology Research
Immunology, Inflammation and Autoimmunity Research
Intracellular Signaling Molecules
Developmental Biology Research
Mutagenesis and Transgenesis: Cre-lox System
Tissue/Cell Markers: Cre-lox System
|Allele Name||targeted mutation 1, Martin McMahon|
|Allele Type||Targeted (Conditional ready (e.g. floxed), No functional change)|
|Common Name(s)||BRAFF-V600E; BrafCA;|
|Mutation Made By||Martin McMahon, University of California, San Francisco|
|Strain of Origin||129P2/OlaHsd|
|Site of Expression||intranasal instillation of an adenovirus expressing Cre recombinase results in benign lung tumors that only rarely progress to adenocarcinoma.|
|Expressed Gene||BRAF, B-Raf proto-oncogene, serine/threonine kinase, human|
A targeting vector was designed to insert a loxP site and the human BRAF cDNA covering exons 15-18 into intron 14, along with a floxed neo cassette. A modified exon 15 was engineered into the vector to encode Braf|
|Gene Symbol and Name||Braf, Braf transforming gene|
|Gene Common Name(s)||9930012E13Rik; AA120551; AA387315; AA473386; B-RAF1; BRAF1; Braf transforming gene 2; Braf-2; Braf2; C87398; D6Ertd631e; DNA segment, Chr 6, ERATO Doi 631, expressed; NS7; RAFB1; RIKEN cDNA 9930012E13 gene; expressed sequence AA120551; expressed sequence AA387315; expressed sequence AA473386; expressed sequence C87398;|
Dankort D; Filenova E; Collado M; Serrano M; Jones K; McMahon M. 2007. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21(4):379-84. [PubMed: 17299132] [MGI Ref ID J:121715]
Aytes A; Mitrofanova A; Lefebvre C; Alvarez MJ; Castillo-Martin M; Zheng T; Eastham JA; Gopalan A; Pienta KJ; Shen MM; Califano A; Abate-Shen C. 2014. Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 25(5):638-51. [PubMed: 24823640] [MGI Ref ID J:210591]
Berres ML; Lim KP; Peters T; Price J; Takizawa H; Salmon H; Idoyaga J; Ruzo A; Lupo PJ; Hicks MJ; Shih A; Simko SJ; Abhyankar H; Chakraborty R; Leboeuf M; Beltrao M; Lira SA; Heym KM; Bigley V; Collin M; Manz MG; McClain K; Merad M; Allen CE. 2014. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211(4):669-83. [PubMed: 24638167] [MGI Ref ID J:211690]
Brady DC; Crowe MS; Turski ML; Hobbs GA; Yao X; Chaikuad A; Knapp S; Xiao K; Campbell SL; Thiele DJ; Counter CM. 2014. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509(7501):492-6. [PubMed: 24717435] [MGI Ref ID J:210437]
Burd CE; Sorrentino JA; Clark KS; Darr DB; Krishnamurthy J; Deal AM; Bardeesy N; Castrillon DH; Beach DH; Sharpless NE. 2013. Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell 152(1-2):340-51. [PubMed: 23332765] [MGI Ref ID J:193498]
Charles RP; Iezza G; Amendola E; Dankort D; McMahon M. 2011. Mutationally Activated BRAFV600E Elicits Papillary Thyroid Cancer in the Adult Mouse. Cancer Res 71(11):3863-71. [PubMed: 21512141] [MGI Ref ID J:172205]
Charles RP; Silva J; Iezza G; Phillips WA; McMahon M. 2014. Activating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis. Mol Cancer Res 12(7):979-86. [PubMed: 24770869] [MGI Ref ID J:211098]
Collisson EA; Trejo CL; Silva JM; Gu S; Korkola JE; Heiser LM; Charles RP; Rabinovich BA; Hann B; Dankort D; Spellman PT; Phillips WA; Gray JW; McMahon M. 2012. A central role for RAF-->MEK-->ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov 2(8):685-93. [PubMed: 22628411] [MGI Ref ID J:193065]
Damsky W; Micevic G; Meeth K; Muthusamy V; Curley DP; Santhanakrishnan M; Erdelyi I; Platt JT; Huang L; Theodosakis N; Zaidi MR; Tighe S; Davies MA; Dankort D; McMahon M; Merlino G; Bardeesy N; Bosenberg M. 2015. mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation. Cancer Cell 27(1):41-56. [PubMed: 25584893] [MGI Ref ID J:218894]
Damsky WE; Curley DP; Santhanakrishnan M; Rosenbaum LE; Platt JT; Gould Rothberg BE; Taketo MM; Dankort D; Rimm DL; McMahon M; Bosenberg M. 2011. beta-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas. Cancer Cell 20(6):741-54. [PubMed: 22172720] [MGI Ref ID J:178598]
Dankort D; Curley DP; Cartlidge RA; Nelson B; Karnezis AN; Damsky WE Jr; You MJ; DePinho RA; McMahon M; Bosenberg M. 2009. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41(5):544-52. [PubMed: 19282848] [MGI Ref ID J:151023]
Gonzalez-Sanchez E; Martin-Caballero J; Flores JM; Hernandez-Losa J; Cortes J; Mares R; Barbacid M; Recio JA. 2013. Lkb1 loss promotes tumor progression of BRAF(V600E)-induced lung adenomas. PLoS One 8(6):e66933. [PubMed: 23825589] [MGI Ref ID J:203456]
Hanna SC; Krishnan B; Bailey ST; Moschos SJ; Kuan PF; Shimamura T; Osborne LD; Siegel MB; Duncan LM; O'Brien ET 3rd; Superfine R; Miller CR; Simon MC; Wong KK; Kim WY. 2013. HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases. J Clin Invest 123(5):2078-93. [PubMed: 23563312] [MGI Ref ID J:201460]
Held MA; Curley DP; Dankort D; McMahon M; Muthusamy V; Bosenberg MW. 2010. Characterization of melanoma cells capable of propagating tumors from a single cell. Cancer Res 70(1):388-97. [PubMed: 20048081] [MGI Ref ID J:155731]
Ho PC; Meeth KM; Tsui YC; Srivastava B; Bosenberg MW; Kaech SM. 2014. Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNgamma. Cancer Res 74(12):3205-17. [PubMed: 24736544] [MGI Ref ID J:212454]
Huillard E; Hashizume R; Phillips JJ; Griveau A; Ihrie RA; Aoki Y; Nicolaides T; Perry A; Waldman T; McMahon M; Weiss WA; Petritsch C; James CD; Rowitch DH. 2012. Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A 109(22):8710-5. [PubMed: 22586120] [MGI Ref ID J:184756]
Ittmann M; Huang J; Radaelli E; Martin P; Signoretti S; Sullivan R; Simons BW; Ward JM; Robinson BD; Chu GC; Loda M; Thomas G; Borowsky A; Cardiff RD. 2013. Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res 73(9):2718-36. [PubMed: 23610450] [MGI Ref ID J:197036]
Juan J; Muraguchi T; Iezza G; Sears RC; McMahon M. 2014. Diminished WNT -> beta-catenin -> c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors. Genes Dev 28(6):561-75. [PubMed: 24589553] [MGI Ref ID J:209631]
Kamata T; Dankort D; Kang J; Giblett S; Pritchard CA; McMahon M; Leavitt AD. 2013. Hematopoietic expression of oncogenic BRAF promotes aberrant growth of monocyte-lineage cells resistant to PLX4720. Mol Cancer Res 11(12):1530-41. [PubMed: 24152792] [MGI Ref ID J:206521]
Knight DA; Ngiow SF; Li M; Parmenter T; Mok S; Cass A; Haynes NM; Kinross K; Yagita H; Koya RC; Graeber TG; Ribas A; McArthur GA; Smyth MJ. 2013. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest 123(3):1371-81. [PubMed: 23454771] [MGI Ref ID J:196375]
Krishnaswami SR; Kumar S; Ordoukhanian P; Yu BD. 2015. Fate and Plasticity of the Epidermis in Response to Congenital Activation of BRAF. J Invest Dermatol 135(2):481-9. [PubMed: 25202828] [MGI Ref ID J:218061]
Landrette SF; Cornett JC; Ni TK; Bosenberg MW; Xu T. 2011. piggyBac transposon somatic mutagenesis with an activated reporter and tracker (PB-SMART) for genetic screens in mice. PLoS One 6(10):e26650. [PubMed: 22039523] [MGI Ref ID J:179725]
Le Mercier I; Chen W; Lines JL; Day M; Li J; Sergent P; Noelle RJ; Wang L. 2014. VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res 74(7):1933-44. [PubMed: 24691994] [MGI Ref ID J:210809]
Lee EK; Lian Z; D'Andrea K; Letrero R; Sheng W; Liu S; Diehl JN; Pytel D; Barbash O; Schuchter L; Amaravaradi R; Xu X; Herlyn M; Nathanson KL; Diehl JA. 2013. The FBXO4 tumor suppressor functions as a barrier to BRAFV600E-dependent metastatic melanoma. Mol Cell Biol 33(22):4422-33. [PubMed: 24019069] [MGI Ref ID J:206100]
Maertens O; Johnson B; Hollstein P; Frederick DT; Cooper ZA; Messiaen L; Bronson RT; McMahon M; Granter S; Flaherty K; Wargo JA; Marais R; Cichowski K. 2013. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov 3(3):338-49. [PubMed: 23171796] [MGI Ref ID J:198252]
Marsh Durban V; Deuker MM; Bosenberg MW; Phillips W; McMahon M. 2013. Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma. J Clin Invest 123(12):5104-18. [PubMed: 24200692] [MGI Ref ID J:207627]
McFadden DG; Vernon A; Santiago PM; Martinez-McFaline R; Bhutkar A; Crowley DM; McMahon M; Sadow PM; Jacks T. 2014. p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer. Proc Natl Acad Sci U S A 111(16):E1600-9. [PubMed: 24711431] [MGI Ref ID J:208854]
Mitra D; Luo X; Morgan A; Wang J; Hoang MP; Lo J; Guerrero CR; Lennerz JK; Mihm MC; Wargo JA; Robinson KC; Devi SP; Vanover JC; D'Orazio JA; McMahon M; Bosenberg MW; Haigis KM; Haber DA; Wang Y; Fisher DE. 2012. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 491(7424):449-53. [PubMed: 23123854] [MGI Ref ID J:189208]
Muinonen-Martin AJ; Susanto O; Zhang Q; Smethurst E; Faller WJ; Veltman DM; Kalna G; Lindsay C; Bennett DC; Sansom OJ; Herd R; Jones R; Machesky LM; Wakelam MJ; Knecht DA; Insall RH. 2014. Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal. PLoS Biol 12(10):e1001966. [PubMed: 25313567] [MGI Ref ID J:217702]
Ni TK; Landrette SF; Bjornson RD; Bosenberg MW; Xu T. 2013. Low-copy piggyBac transposon mutagenesis in mice identifies genes driving melanoma. Proc Natl Acad Sci U S A 110(38):E3640-9. [PubMed: 24003131] [MGI Ref ID J:201160]
Sayin VI; Ibrahim MX; Larsson E; Nilsson JA; Lindahl P; Bergo MO. 2014. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med 6(221):221ra15. [PubMed: 24477002] [MGI Ref ID J:212506]
Scortegagna M; Ruller C; Feng Y; Lazova R; Kluger H; Li JL; De SK; Rickert R; Pellecchia M; Bosenberg M; Ronai ZA. 2014. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. Oncogene 33(34):4330-9. [PubMed: 24037523] [MGI Ref ID J:214355]
Strohecker AM; Guo JY; Karsli-Uzunbas G; Price SM; Chen GJ; Mathew R; McMahon M; White E. 2013. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov 3(11):1272-85. [PubMed: 23965987] [MGI Ref ID J:206987]
Tabor V; Bocci M; Alikhani N; Kuiper R; Larsson LG. 2014. MYC synergizes with activated BRAFV600E in mouse lung tumor development by suppressing senescence. Cancer Res 74(16):4222-9. [PubMed: 24934810] [MGI Ref ID J:213723]
Tang N; Marshall WF; McMahon M; Metzger RJ; Martin GR. 2011. Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Science 333(6040):342-5. [PubMed: 21764747] [MGI Ref ID J:174194]
Tien AC; Tsai HH; Molofsky AV; McMahon M; Foo LC; Kaul A; Dougherty JD; Heintz N; Gutmann DH; Barres BA; Rowitch DH. 2012. Regulated temporal-spatial astrocyte precursor cell proliferation involves BRAF signalling in mammalian spinal cord. Development 139(14):2477-87. [PubMed: 22675209] [MGI Ref ID J:185602]
Trejo CL; Green S; Marsh V; Collisson EA; Iezza G; Phillips WA; McMahon M. 2013. Mutationally activated PIK3CA(H1047R) cooperates with BRAF(V600E) to promote lung cancer progression. Cancer Res 73(21):6448-61. [PubMed: 24019382] [MGI Ref ID J:204513]
Trejo CL; Juan J; Vicent S; Sweet-Cordero A; McMahon M. 2012. MEK1/2 inhibition elicits regression of autochthonous lung tumors induced by KRASG12D or BRAFV600E. Cancer Res 72(12):3048-59. [PubMed: 22511580] [MGI Ref ID J:189336]
Wang J; Kobayashi T; Floc'h N; Kinkade CW; Aytes A; Dankort D; Lefebvre C; Mitrofanova A; Cardiff RD; McMahon M; Califano A; Shen MM; Abate-Shen C. 2012. B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer. Cancer Res 72(18):4765-76. [PubMed: 22836754] [MGI Ref ID J:191327]
Yuan P; Ito K; Perez-Lorenzo R; Del Guzzo C; Lee JH; Shen CH; Bosenberg MW; McMahon M; Cantley LC; Zheng B. 2013. Phenformin enhances the therapeutic benefit of BRAFV600E inhibition in melanoma. Proc Natl Acad Sci U S A 110(45):18226-31. [PubMed: 24145418] [MGI Ref ID J:202916]
Animal Health ReportsRoom Number FGB27
Breeding & Husbandry When maintaining a live colony, these mice can be bred as homozygous for the Braftm1Mmcm allele. Mating System Homozygote x Homozygote (Female x Male) 08-APR-13 Diet Information LabDiet® 5K20
To request more information use the Customer Support Contact Form or call 1-800-422-6423 or 1-207-288-5845
View All Strains Awaiting Transfer from the Donor, In Progress and On Hold
|Pricing for USA, Canada and Mexico shipping destinations|
Price per mouse (US dollars $) Gender Genotypes Provided Individual Mouse $239.00 Female or Male Homozygous for Braftm1Mmcm
Price per Pair (US dollars $) Pair Genotype $478.00 Homozygous for Braftm1Mmcm x Homozygous for Braftm1Mmcm
This strain is currently on HOLD - Contact Customer Service for more information.
|Pricing for International shipping destinations|
Price per mouse (US dollars $) Gender Genotypes Provided Individual Mouse $310.70 Female or Male Homozygous for Braftm1Mmcm
Price per Pair (US dollars $) Pair Genotype $621.40 Homozygous for Braftm1Mmcm x Homozygous for Braftm1Mmcm
This strain is currently on HOLD - Contact Customer Service for more information.
|Considerations for Choosing Controls|
|Control Pricing Information for Genetically Engineered Mutant Strains.|
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