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

Nature Genetics volume 22, pages 44–52 (1999)Cite this article

Abstract

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 β-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 β-islet cells. These results establish Cdk4 as an essential regulator of specific cell types.

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Figure 1: Generation of Cdk4neo/neo mice.
Figure 2: Defective reproductive organs in Cdk4neo/neo mice.
Figure 3: Insulin-dependent diabetes in Cdk4neo/neo mice.
Figure 4: Defective pancreatic β-cell development in Cdk4neo/neo mice.
Figure 5: Reduced islet area in Cdk4neo/neo mice and islet hyperplasia in Cdk4R24C/R24C mice.
Figure 6: Generation of mice expressing Cdk4R24C.
Figure 7: Deregulation of Cdk4 activity results in testicular Leydig cell and pancreatic β-islet cell hyperplasia.

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Acknowledgements

We thank R. Nicosia for his assistance with morphometric analysis and B. Elfenbien with pancreatic histology. This work was initiated when S.G.R., P.D., E.J.G. and M.B. were at the Bristol-Myers Squibb Pharmaceutical Research Institute. S.G.R. was partially supported by a FELS Foundation Grant awarded to E.P.R. P.D. was supported by a fellowship from the Association pour la Recherche sur le Cancer and by a grant from La Ligue Nationale Contre le Cancer de la Région Aquitaine. G.B. was supported by NIH grants RO1-AG-07988, RO1-AA-10221 and RR-00349. M.B. was partially supported by a grant from Pfizer S.A., Spain.

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Author notes

  1. Sushil G. Rane and Pierre Dubus: These authors contributed equally to this work.

Authors and Affiliations

  1. Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, 19140, Pennsylvania, USA

    Sushil G. Rane, Richard V. Mettus & E. Premkumar Reddy

  2. Laboratoire d'Histologie–Embryologie, Université Victor Ségalen, Bordeaux 2, Cedex, 33076, France

    Pierre Dubus

  3. Eli Lilly & Co., 639 S. Delaware, Indianapolis, 46285, Indiana, USA

    Elizabeth J. Galbreath

  4. Division of Endocrinology, Diabetes and Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, 19140, Pennsylvania, USA

    Guenther Boden

  5. Centro Nacional de Investigaciones Oncológicas Carlos III, Ctra. Majadahonda-Pozuelo km.2, Majadahonda, 28220, Madrid, Spain

    Mariano Barbacid

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  1. Sushil G. Rane
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Correspondence to E. Premkumar Reddy or Mariano Barbacid.

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Rane, S., Dubus, P., Mettus, R. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat Genet 22, 44–52 (1999). https://doi.org/10.1038/8751

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