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Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia.

To ascertain the role of cyclin-dependent kinase 4 (Cdk4) in vivo, we have targeted the mouse Cdk4 locus by homologous recombination to generate two strains of mice, one that lacks Cdk4 expression and one that expresses a Cdk4 molecule with an activating mutation. Embryonic fibroblasts proliferate normally in the absence of Cdk4 but have a delayed S phase on re-entry into the cell cycle. Moreover, mice devoid of Cdk4 are viable, but small in size and infertile. These mice also develop insulin-deficient diabetes due to a reduction in beta-islet pancreatic cells. In contrast, mice expressing a mutant Cdk4 that cannot bind the cell-cycle inhibitor P16INK4a display pancreatic hyperplasia due to abnormal proliferation of beta-islet cells. These results establish Cdk4 as an essential regulator of specific cell types.

Pubmed ID: 10319860

Authors

  • Rane SG
  • Dubus P
  • Mettus RV
  • Galbreath EJ
  • Boden G
  • Reddy EP
  • Barbacid M

Journal

Nature genetics

Publication Data

May 25, 1999

Associated Grants

  • Agency: NIAAA NIH HHS, Id: R01-AA-10221
  • Agency: NIA NIH HHS, Id: R01-AG-07988
  • Agency: NCRR NIH HHS, Id: RR-00349

Mesh Terms

  • Animals
  • Cell Line
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • Diabetes Mellitus
  • Enzyme Activation
  • Female
  • Gene Expression Regulation
  • Hyperplasia
  • Infertility, Female
  • Infertility, Male
  • Insulin
  • Islets of Langerhans
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mutagenesis, Site-Directed
  • Proto-Oncogene Proteins
  • Spermatogenesis