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Induced Expression of p16INK4a Inhibits Both CDK4- and CDK2-Associated Kinase Activity by Reassortment of Cyclin-CDK-Inhibitor Complexes
Open accessAbstract
To investigate the mode of action of the p16(INK4a) tumor suppressor protein, we have established U2-OS cells in which the expression of p16(INK4a) can be regulated by addition or removal of isopropyl-beta-D-thiogalactopyranoside. As expected, induction of p16(INK4a) results in a G1 cell cycle arrest by inhibiting phosphorylation of the retinoblastoma protein (pRb) by the cyclin-dependent kinases CDK4 and CDK6. However, induction of p16(INK4a) also causes marked inhibition of CDK2 activity. In the case of cyclin E-CDK2, this is brought about by reassortment of cyclin, CDK, and CDK-inhibitor complexes, particularly those involving p27(KIP1). Size fractionation of the cellular lysates reveals that a substantial proportion of CDK4 participates in active kinase complexes of around 200 kDa. Upon induction of p16(INK4a), this complex is partly dissociated, and the majority of CDK4 is found in lower-molecular-weight fractions consistent with the formation of a binary complex with p16(INK4a). Sequestration of CDK4 by p16(INK4a) allows cyclin D1 to associate increasingly with CDK2, without affecting its interactions with the CIP/KIP inhibitors. Thus, upon the induction of p16(INK4a), p27(KIP1) appears to switch its allegiance from CDK4 to CDK2, and the accompanying reassortment of components leads to the inhibition of cyclin E-CDK2 by p27(KIP1) and p21(CIP1). Significantly, p16(INK4a) itself does not appear to form higher-order complexes, and the overwhelming majority remains either free or forms binary associations with CDK4 and CDK6.
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“Indeed, p16 upregulation in the presence of p21 synergistically induces irreversible cell cycle arrest by inhibiting both CDK2 and CDK4/6 [32].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [32]
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Metadata
- Authors
- McConnell, B. B., Gregory, F. J., Stott, F. J., Hara, E., & Peters, G.
- Affiliations
- Imperial Cancer Research Fund Laboratories, London WC2A 3PX, United Kingdom
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1999-03-01
- Volume
- 19
- Issue
- 3
- Pages
- 1981-1989
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC83991
- OpenAlex
- W1923683854
- Cited by
- 238
- References
- 81
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 4 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 3 · 2019: 6 · 2017: 10 · 2016: 5 · 2015: 6 · 2014: 7 · 2013: 5 · 2012: 8
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- p16INK4a, CDK4, CDK2, cyclin-dependent kinase inhibition, p27, p21, cyclin E, cyclin D1, retinoblastoma protein phosphorylation, G1 cell cycle arrest, tumor suppressor mechanism, U2OS cells, inducible gene expression
- MeSH terms
- Cell Cycle, Cell Division, Enzyme Inhibitors, Humans, Microtubule-Associated Proteins, Proto-Oncogene Proteins, Time Factors, Tumor Cells, Cultured, Cyclins, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, CDC2-CDC28 Kinases, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4
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