Targeted Disruption of CDK4 Delays Cell Cycle Entry with Enhanced p27 Kip1 Activity
Open accessAbstract
The mechanism by which cyclin-dependent kinase 4 (CDK4) regulates cell cycle progression is not entirely clear. Cyclin D/CDK4 appears to initiate phosphorylation of retinoblastoma protein (Rb) leading to inactivation of the S-phase-inhibitory action of Rb. However, cyclin D/CDK4 has been postulated to act in a noncatalytic manner to regulate the cyclin E/CDK2-inhibitory activity of p27(Kip1) by sequestration. In this study we investigated the roles of CDK4 in cell cycle regulation by targeted disruption of the mouse CDK4 gene. CDK4(-/-) mice survived embryogenesis and showed growth retardation and reproductive dysfunction associated with hypoplastic seminiferous tubules in the testis and perturbed corpus luteum formation in the ovary. These phenotypes appear to be opposite to those of p27-deficient mice such as gigantism and gonadal hyperplasia. A majority of CDK4(-/-) mice developed diabetes mellitus by 6 weeks, associated with degeneration of pancreatic islets. Fibroblasts from CDK4(-/-) mouse embryos proliferated similarly to wild-type embryonic fibroblasts under conditions that promote continuous growth. However, quiescent CDK4(-/-) fibroblasts exhibited a substantial ( approximately 6-h) delay in S-phase entry after serum stimulation. This cell cycle perturbation by CDK4 disruption was associated with increased binding of p27 to cyclin E/CDK2 and diminished activation of CDK2 accompanied by impaired Rb phosphorylation. Importantly, fibroblasts from CDK4(-/-) p27(-/-) embryos displayed partially restored kinetics of the G(0)-S transition, indicating the significance of the sequestration of p27 by CDK4. These results suggest that at least part of CDK4's participation in the rate-limiting mechanism for the G(0)-S transition consists of controlling p27 activity.
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Predicted side effects of targeted therapy may involve glucose intolerance based on pancreatic β-cell requirements for CDK4 and p16INK4a effects on islet regeneration.
“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 [86]
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“The absence of these phenotypes with Cdk4 KD was consistent with a lack of gross abnormality in Cdk4−/− mouse muscle (Rane et al., 1999; Tsutsui et al., 1999).”
BackgroundHypoplasia of endocrine and exocrine pancreas in homozygous transgenic TGF-β1
Moritani, M., Yamasaki, S., Kagami, M., Suzuki, T., Yamaoka, T., Sano, T., Hata, J.-I., & Itakura, M. (2005) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2004.08.007 · Cited by 37 · see citing works
Postnatal Expansion of the Pancreatic β-Cell Mass Is Dependent on Survivin
Jiang, Y., Nishimura, W., Devor-Henneman, D., Kusewitt, D., Wang, H., Holloway, M. P., Dohi, T., Sabo, E., Robinson, M. L., Altieri, D. C., et al. (2008) · Diabetes · doi:10.2337/db08-0170 · Cited by 38 · see citing works
Role of Cdk4 in lymphocyte function and allergen response
Chow, Y. H., Zhu, X. D., Liu, L., Schwartz, B. R., Huang, X. Z., Harlan, J. M., & Schnapp, L. M. (2010) · Cell Cycle · doi:10.4161/cc.9.24.14209 · Cited by 15 · see citing works
- Authors
- Tsutsui, T., Hesabi, B., Moons, D. S., Pandolfi, P. P., Hansel, K. S., Koff, A., & Kiyokawa, H.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Department of Human Genetics
- Memorial Sloan Kettering Cancer Center (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1999-10
- Volume
- 19
- Issue
- 10
- Pages
- 7011-7019
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC84696
- OpenAlex
- W1932315029
- Cited by
- 395
- References
- 64
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 12 · 2014: 16 · 2013: 11 · 2012: 18
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- National Institute of General Medical Sciences (GM 52597, R01GM052597)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- CDK4, p27, cell cycle regulation, retinoblastoma protein phosphorylation, cyclin E/CDK2, diabetes mellitus, corpus luteum formation, fibroblast proliferation, S phase entry
- MeSH terms
- Animals, Atrophy, Cell Cycle, Corpus Luteum, Diabetes Mellitus, Female, Glycosuria, Homozygote, Male, Mice, Mutant Strains, Microtubule-Associated Proteins, Protein Binding, Proto-Oncogene Proteins, Seminiferous Tubules, Tissue Distribution, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cyclin-Dependent Kinases, Tumor Suppressor Proteins, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice
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