K-ras is an essential gene in the mouse with partial functional overlap with N-ras (original) (raw)

  1. Leisa Johnson1,
  2. Doron Greenbaum1,
  3. Karen Cichowski1,
  4. Kim Mercer1,2,
  5. Elizabeth Murphy1,3,
  6. Eric Schmitt1,
  7. Roderick T. Bronson4,
  8. Heywood Umanoff5,
  9. Windfried Edelmann5,
  10. Raju Kucherlapati5, and
  11. Tyler Jacks1,2,6
  12. 1Department of Biology, and 2Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139;3Department of Medicine, University of California at San Francisco, San Francisco, California 94143; 4Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111; 5Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461 USA

Abstract

Mammalian ras genes are thought to be critical in the regulation of cellular proliferation and differentiation and are mutated in ∼30% of all human tumors. However, N-ras and H-ras are nonessential for mouse development. To characterize the normal role of K-ras in growth and development, we have mutated it by gene targeting in the mouse. On an inbred genetic background, embryos homozygous for this mutation die between 12 and 14 days of gestation, with fetal liver defects and evidence of anemia. Thus, K-ras is the only member of the ras gene family essential for mouse embryogenesis. We have also investigated the effect of multiple mutations within the ras gene family. Most animals lacking N-ras function and heterozygous for the K-_ras_mutation exhibit abnormal hematopoietic development and die between days 10 and 12 of embryogenesis. Thus, partial functional overlap appears to occur within the ras gene family, but K-_ras_provides a unique and essential function.

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