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A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E.
Cancer Res. 2005 Aug 01; 65(15):6631-9.CR

Abstract

A mouse model of gastrointestinal stromal tumor (GIST) has been developed by a knock-in gene targeting strategy, which introduced a Kit gene K641E mutation, originally identified in sporadic human GISTs and in the germ line of familial GIST syndrome patients. Homozygous and heterozygous Kit K641E mice develop gastrointestinal pathology with complete penetrance and all Kit K641E homozygotes die by age 30 weeks due to gastrointestinal obstruction by hyperplastic interstitial cells of Cajal (ICC) or GISTs. Heterozygous mice have less extensive ICC hyperplasia and smaller GISTs, suggesting a dose-response relationship between oncogenically activated Kit and ICC proliferation. Immunoprecipitation and Western blotting reveal GISTs to contain abundant phosphorylated/activated Kit. In addition to ICC hyperplasia and GISTs, homozygous Kit K641E mice exhibit loss-of-function Kit phenotypes, including white coat color, decreased numbers of dermal mast cells, and sterility, indicating that despite its oncogenic activity the mutant form cannot accomplish many activities of the wild-type gene. Kit K641E reproduces the pathology associated with the familial GIST syndrome and thus is an excellent model to study Kit pathway activation, ICC biology, GIST pathogenesis, and preclinical validations of GIST therapies and mechanisms of drug resistance.

Authors+Show Affiliations

Department of Pathology, University of Washington Medical Center, Seattle, Washington 98195, USA. bprubin@u.washington.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16061643

Citation

Rubin, Brian P., et al. "A Knock-in Mouse Model of Gastrointestinal Stromal Tumor Harboring Kit K641E." Cancer Research, vol. 65, no. 15, 2005, pp. 6631-9.
Rubin BP, Antonescu CR, Scott-Browne JP, et al. A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E. Cancer Res. 2005;65(15):6631-9.
Rubin, B. P., Antonescu, C. R., Scott-Browne, J. P., Comstock, M. L., Gu, Y., Tanas, M. R., Ware, C. B., & Woodell, J. (2005). A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E. Cancer Research, 65(15), 6631-9.
Rubin BP, et al. A Knock-in Mouse Model of Gastrointestinal Stromal Tumor Harboring Kit K641E. Cancer Res. 2005 Aug 1;65(15):6631-9. PubMed PMID: 16061643.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E. AU - Rubin,Brian P, AU - Antonescu,Cristina R, AU - Scott-Browne,James P, AU - Comstock,Melissa L, AU - Gu,Yansong, AU - Tanas,Munir R, AU - Ware,Carol B, AU - Woodell,Jessica, PY - 2005/8/3/pubmed PY - 2005/10/5/medline PY - 2005/8/3/entrez SP - 6631 EP - 9 JF - Cancer research JO - Cancer Res VL - 65 IS - 15 N2 - A mouse model of gastrointestinal stromal tumor (GIST) has been developed by a knock-in gene targeting strategy, which introduced a Kit gene K641E mutation, originally identified in sporadic human GISTs and in the germ line of familial GIST syndrome patients. Homozygous and heterozygous Kit K641E mice develop gastrointestinal pathology with complete penetrance and all Kit K641E homozygotes die by age 30 weeks due to gastrointestinal obstruction by hyperplastic interstitial cells of Cajal (ICC) or GISTs. Heterozygous mice have less extensive ICC hyperplasia and smaller GISTs, suggesting a dose-response relationship between oncogenically activated Kit and ICC proliferation. Immunoprecipitation and Western blotting reveal GISTs to contain abundant phosphorylated/activated Kit. In addition to ICC hyperplasia and GISTs, homozygous Kit K641E mice exhibit loss-of-function Kit phenotypes, including white coat color, decreased numbers of dermal mast cells, and sterility, indicating that despite its oncogenic activity the mutant form cannot accomplish many activities of the wild-type gene. Kit K641E reproduces the pathology associated with the familial GIST syndrome and thus is an excellent model to study Kit pathway activation, ICC biology, GIST pathogenesis, and preclinical validations of GIST therapies and mechanisms of drug resistance. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16061643/A_knock_in_mouse_model_of_gastrointestinal_stromal_tumor_harboring_kit_K641E_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16061643 DB - PRIME DP - Unbound Medicine ER -