Abstract
Lack of Cdk4 expression in mice leads to insulin-deficient diabetes and female infertility owing to a reduced number of pancreatic β cells and prolactin-producing pituitary lactotrophs, respectively. Cdk4 null mice display also reduced body and organ size. Here, we show that Cdk4 is essential for the postnatal proliferation of pancreatic β cells but not for embryonic neogenesis from ductal epithelial cells. Re-expression of endogenous Cdk4 in β cells and in the pituitary gland of Cdk4 null mice restores cell proliferation and results in fertile and normoglycemic animals, thus, demonstrating that the proliferation defects in these cellular populations are cell autonomous because of the lack of Cdk4 expression. However, these mice remain small in size, indicating that this phenotype is not because of pancreatic- or pituitary-mediated endocrine defects. This phenotype is a consequence of reduced cell numbers rather than reduced cell size. Thus, mammalian Cdk4 is not only involved in controlling proliferation of specific cell types but may play a wider role in establishing homeostatic cell numbers.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bonner-Weir S . (2000a). J. Mol. Endocrinol., 24, 297–302.
Bonner-Weir S . (2000b). Trend. Endocrinol. Metab., 11, 375–378.
Dyson N . (1998). Genes Dev., 12, 2245–2262.
Fantl V, Stamp G, Andrews A, Rosewell I and Dickson C . (1995). Genes Dev., 9, 2364–2372.
Finegood DT, Scaglia L and Bonner-Weir S . (1995). Diabetes, 44, 249–256.
Franklin DS, Godfrey VL, O'Brien DA, Deng C and Xiong Y . (2000). Mol. Cell. Biol., 20, 6147–6158.
Gannon M, Shiota C, Postic C, Wright CVE and Magnuson M . (2000). Genesis, 26, 139–142.
Herrera PL, Huarte J, Sanvito F, Meda P, Orci L and Vassalli J-D . (1991). Development, 113, 1257–1265.
Kim SK and Hebrok M . (2001). Genes Dev., 15, 111–127.
Kulkarni RH, Brüning JC, Winnay JN, Postic C, Magnuson MA and Kahn CR . (1999). Cell, 96, 329–339.
Latres E, Malumbres M, Sotillo R, Martín J, Ortega S, Martín-Caballero J, Flores JM, Cordón-Cardo C and Barbacid M . (2000). EMBO J., 19, 3496–3506.
Lundberg AS and Weinberg RA . (1998). Mol. Cell. Biol., 18, 753–761.
Malumbres M and Barbacid M . (2001). Nat. Rev. Cancer, 1, 222–231.
Meyer CA, Jacobs HW, Datar SA, Du W, Edgar BA and Lehner CF . (2000). EMBO J., 19, 4533–4542.
Montanya E, Nacher V, Biarnes M and Soler J . (2000). Diabetes, 49, 1341–1346.
Moons DS, Jirawatnotai S, Tsutsui T, Franks R, Parlow AF, Hales DB, Gibori G, Fazleabas AT and Kiyokawa H . (2002a). Endocrinology, 143, 647–654.
Moons DS, Jirawatnotai S, Parlow AF, Gibori G, Kineman RD and Kiyokawa H . (2002b). Endocrinology, 143, 3001–3008.
Morgan DO . (1995). Nature, 374, 131–134.
Nevins JR . (1998). Cell Growth Differentiation, 9, 585–593.
Pardee AB . (1989). Science, 246, 603–608.
Pavletich NP . (1999). J. Mol. Biol., 287, 821–828.
Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD and Magnuson MA . (1999). J. Biol. Chem., 274, 305–315.
Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP and Barbacid M . (1999). Nat. Genet., 22, 44–52.
Reed SI . (1997). Cancer Survey, 29, 7–23.
Ruas M and Peters G . (1998). Biochem. Biophys. Acta, 1378, F115–F177.
Sherr CJ . (2000). Cancer Res., 60, 3689–3695.
Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.
Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ and Weinberg RA . (1995). Cell, 82, 621–630.
Sotillo R, Dubus P, Martin J, De la Cueva E, Ortega S, Malumbres M and Barbacid M . (2001a). EMBO J., 20, 6637–6647.
Sotillo R, García JF, Ortega S, Martín J, Dubus P, Barbacid M and Malumbres M . (2001b). Proc. Natl. Acad. Sci. USA, 98, 13312–13317.
Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A and Kiyokawa H . (1999). Mol. Cell. Biol., 19, 7011–7019.
Weinberg RA . (1995). Cell, 81, 323–330.
Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Buschenfelde KH and Beach D . (1995). Science, 269, 1281–1284.
Zuo L, Wedger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N and Dracopoli NC . (1996). Nat. Genet., 12, 97–99.
Acknowledgements
We thank Ernesto de la Cueva, Maribel Muñoz, Marta San Román, Ignacio Segovia, Michelle Turmo and Raquel Villar for their excellent technical assistance. This work was supported by Grants from the Spanish Ministerio of Educación y Cultura (to SO and MB), Ligue contre le Cancer (Comité de Dordogne) and INSERM (to PD) and Fundación Pfizer (to MB). JM and RS were supported in part by fellowships from the Fondo de Investigación Sanitaria, SLH by a postdoctoral fellowship from the Comunidad Autónoma de Madrid and FN-P by a fellowship from the Foundation pour la Recherche Médicale.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Martín, J., Hunt, S., Dubus, P. et al. Genetic rescue of Cdk4 null mice restores pancreatic β-cell proliferation but not homeostatic cell number. Oncogene 22, 5261–5269 (2003). https://doi.org/10.1038/sj.onc.1206506
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206506
Keywords
This article is cited by
-
The cell cycle as a brake for β-cell regeneration from embryonic stem cells
Stem Cell Research & Therapy (2016)
-
Islet biology, the CDKN2A/B locus and type 2 diabetes risk
Diabetologia (2016)
-
MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2
Oncogene (2015)
-
The regulation of pre- and post-maturational plasticity of mammalian islet cell mass
Diabetologia (2014)
-
Cell cycle kinases as therapeutic targets for cancer
Nature Reviews Drug Discovery (2009)