The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
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]
Citations
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Disruption of IRS-2 causes type 2 diabetes in mice
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Knights, C. D., & Pestell, R. G. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-337-0_1
Maintaining glucose homeostasis in response to aging and stress: The role of Pcif1, Bmi1, and Pdx1
Cannon, C. E. (2014) · ScholarlyCommons (University of Pennsylvania)
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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