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Somatic activation of the K-ras oncogene causes early onset lung cancer in mice

Author

Listed:
  • Leisa Johnson

    (Massachusetts Institute of Technology, and
    Onyx Pharmaceuticals)

  • Kim Mercer

    (Massachusetts Institute of Technology, and
    Howard Hughes Medical Institute, Center for Cancer Research)

  • Doron Greenbaum

    (Massachusetts Institute of Technology, and
    University of California at San Francisco)

  • Roderick T. Bronson

    (Tufts University Schools of Medicine and Veterinary Medicine)

  • Denise Crowley

    (Massachusetts Institute of Technology, and
    Howard Hughes Medical Institute, Center for Cancer Research)

  • David A. Tuveson

    (Massachusetts Institute of Technology, and
    Howard Hughes Medical Institute, Center for Cancer Research
    Dana-Farber Cancer Institute)

  • Tyler Jacks

    (Massachusetts Institute of Technology, and
    Howard Hughes Medical Institute, Center for Cancer Research)

Abstract

About 30% of human tumours carry ras gene mutations1,2. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas (∼70–90% incidence), colon (∼50%) and lung (∼25–50%)1,2,3,4,5,6. To constuct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

Suggested Citation

  • Leisa Johnson & Kim Mercer & Doron Greenbaum & Roderick T. Bronson & Denise Crowley & David A. Tuveson & Tyler Jacks, 2001. "Somatic activation of the K-ras oncogene causes early onset lung cancer in mice," Nature, Nature, vol. 410(6832), pages 1111-1116, April.
    • Handle: RePEc:nat:nature:v:410:y:2001:i:6832:d:10.1038_35074129
    DOI: 10.1038/35074129
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    Cited by:

    1. Fayang Ma & Kyle Laster & Zigang Dong, 2022. "The comparison of cancer gene mutation frequencies in Chinese and U.S. patient populations," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Fernando C. Baltanás & Rósula García-Navas & Pablo Rodríguez-Ramos & Nuria Calzada & Cristina Cuesta & Javier Borrajo & Rocío Fuentes-Mateos & Andrea Olarte-San Juan & Nerea Vidaña & Esther Castellano, 2023. "Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Andreas Weigert & Xiang Zheng & Alina Nenzel & Kati Turkowski & Stefan Günther & Elisabeth Strack & Evelyn Sirait-Fischer & Eiman Elwakeel & Ivan M. Kur & Vandana S. Nikam & Chanil Valasarajan & Hauke, 2022. "Fibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    4. Yao-Zhong Liu & Charles A Miller & Yan Zhuang & Sudurika S Mukhopadhyay & Shigeki Saito & Edward B. Overton & Gilbert F Morris, 2020. "The Impact of the Deepwater Horizon Oil Spill upon Lung Health—Mouse Model-Based RNA-Seq Analyses," IJERPH, MDPI, vol. 17(15), pages 1-23, July.
    5. Wenbin Xu & Han Yao & Zhen Wu & Xiaojun Yan & Zishan Jiao & Yajing Liu & Meng Zhang & Donglai Wang, 2024. "Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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