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Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia
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 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.
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“For instance, when cell cycle arrest is induced specifically in β-cells by overexpression of p27 [24] or by deletion of Cdk4 postnatally, β-cell mass decreases or fails to expand, which would not be the case if neogenesis or transdifferentiation were major sources of new β-cells [25,26].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [25]
In the citing paper
“CDKN2A is a known tumour suppressor and its product, p16INK4a, inhibits CDK4 (cyclin-dependent kinase 4), a powerful regulator of pancreatic beta cell replication (19-21).”
From Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes (2007) · cites this paper as [19]
In the citing paper
“predicted side effects of targeted therapy may involve glucose intolerance, based on requirements of pancreatic β-cells for CDK4 (85, 86) and effects of p16INK4a on age-dependent islet cell regeneration (87)”
From Targeting CDK4 and CDK6: From Discovery to Therapy (2016) · cites this paper as [85]
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Crabtree, J. S., Scacheri, P. C., Ward, J. M., McNally, S. R., Swain, G. P., Montagna, C., Hager, J. H., Hanahan, D., Edlund, H., Magnuson, M. A., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.17.6075-6085.2003 · Cited by 256
“cdk4 knockout animals (30), on the other hand, are significantly smaller than wild-type littermates and develop insulin- deficient diabetes at an early age.”
BackgroundInfluentialCho, Y. M., Kim, T. H., Lim, S., Choi, S. H., Shin, H. D., Lee, H. K., Park, K. S., & Jang, H. C. (2009) · Diabetologia · doi:10.1007/s00125-008-1196-4 · Cited by 243
CDK inhibitors in cancer therapy: what is next?
Malumbres, M., Pevarello, P., Barbacid, M., & Bischoff, J. R. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.10.012 · Cited by 240
Self-citationOsteocalcin Promotes β-Cell Proliferation During Development and Adulthood Through Gprc6a
Wei, J., Hanna, T., Suda, N., Karsenty, G., & Ducy, P. F. (2013) · Diabetes · doi:10.2337/db13-0887 · Cited by 237
Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression
Lee, Y., Dominy, J. E., Choi, Y. J., Jurczak, M., Tolliday, N., Camporez, J. P., Chim, H., Lim, J.-H., Ruan, H.-B., Yang, X., et al. (2014) · Nature · doi:10.1038/nature13267 · Cited by 234
Killing cells by targeting mitosis
Manchado, E., Guillamot, M., & Malumbres, M. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2011.197 · Cited by 233
Priorities for Improving the Management of Gastroenteropancreatic Neuroendocrine Tumors
Modlin, I. M., Moss, S. F., Chung, D. C., Jensen, R. T., & Snyderwine, E. G. (2008) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djn275 · Cited by 224
Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice
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Cyclin D-CDK4/6 functions in cancer
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Physiological Relevance of Cell Cycle Kinases
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“In quiescent hair follicle stem cells, Cdk4 is repressed by the nuclear factor of activated T cells c1 (NFATc1).”
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Wide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
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Diabetes mellitus—advances and challenges in human β-cell proliferation
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Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell
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CDK4: A Key Player in the Cell Cycle, Development, and Cancer
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“Moreover, CDK4-null mice are smaller in size and infertile.(25,26)”
BackgroundDrosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression
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Therapeutic Targeting of the Cyclin D3:CDK4/6 Complex in T Cell Leukemia
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“…and progression of T cell leukemia and, at the same time, cause minimal hematologic side effects, based on the phenotypes of animals lacking expression of cyclin D3 or CDK4/6 (Cooper et al., 2006; Malumbres et al., 2004; Rane et al., 1999; Sicinska et al., 2003, 2006; Tsutsui et al., 1999).”
Type 2 Diabetes and the Aging Pancreatic Beta Cell
Gunasekaran, U., & GANNON, M. A. (2011) · Aging · doi:10.18632/aging.100350 · Cited by 190
Cyclin D1 Determines Mitochondrial Function InVivo
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“The cdk4 / 3T3 fibroblasts were previously described (48).”
BackgroundA GRFa2/Prop1/Stem (GPS) Cell Niche in the Pituitary
García-Lavandeira, M., Quereda, V., Flores, I., Sáez, C., Díaz-Rodríguez, E., Japón, M. Á., Ryan, A. K., Blasco, M. A., Diéguez, C., Malumbres, M., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004815 · Cited by 186
“Cdk4-deficient mice in which Cdk4 has been inactivated by the insertion of a neomycin-resistant (neo) cassette [Cdk4(n/n) mice] [48] display hypoplastic pituitaries with a dramatic decrease of all hormonesecretory cells in the AP during postnatal life (Figure 6A–B, center and Figure S4).”
Backgroundβ-cell failure as a complication of diabetes
Chang-Chen, K. J., Mullur, R., & Bernal-Mizrachi, E. (2008) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-008-9101-5 · Cited by 225
“binding by INK4 proteins exhibit islet hyperplasia [15, 18].”
Metadata
- Authors
- Rane, S. G., Dubus, P., Mettus, R. V., Galbreath, E. J., Boden, G., Reddy, E. P., & Barbacid, M.
- Affiliations
- Temple University (US)
- Université Bordeaux Segalen (FR)
- Eli Lilly (United States) (US)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Reddy, E. Premkumar
- Barbacid, Mariano
- Venue
- Nature Genetics
- Published
- 1999-05
- Volume
- 22
- Issue
- 1
- Pages
- 44-52
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- DOI
- 10.1038/8751
- OpenAlex
- W1520222296
- Cited by
- 700
- References
- 44
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 12 · 2023: 15 · 2022: 16 · 2021: 11 · 2020: 23 · 2019: 17 · 2018: 19 · 2017: 28 · 2016: 20 · 2015: 29 · 2014: 33 · 2013: 33 · 2012: 32
- FWCI
- 17.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag007988-10, 5r01aa010221-03)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA-10221)
- National Institute on Aging (R01-AG07988)
- National Center for Research Resources (M01RR000349, RR-00349)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- CDK4, insulin-deficient diabetes, beta-cell hyperplasia, pancreatic islets, p16INK4a, cell cycle regulation, S phase delay, embryonic fibroblasts, infertility, cell proliferation
- MeSH terms
- Animals, Cell Line, Diabetes Mellitus, Enzyme Activation, Female, Gene Expression Regulation, Hyperplasia, Infertility, Female, Infertility, Male, Insulin, Islets of Langerhans, Male, Mice, Inbred Strains, Proto-Oncogene Proteins, Spermatogenesis, Mutagenesis, Site-Directed, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase 4, Mice
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