New functional activities for the p21 family of CDK inhibitors.
Open accessAbstract
The association of cdk4 with D-type cyclins to form functional kinase complexes is comparatively inefficient. This has led to the suggestion that assembly might be a regulated step. In this report we demonstrate that the CDK inhibitors p21(CIP), p27(KIP), and p57(KIP2) all promote the association of cdk4 with the D-type cyclins. This effect is specific and does not occur with other cdk inhibitors or cdk-binding proteins. Both in vivo and in vitro, the abundance of assembled cdk4/cyclin D complex increases directly with increasing inhibitor levels. The promotion of assembly is not attributable to a simple cell cycle block and requires the function of both the cdk and cyclin-binding domains. Kinetic studies demonstrate that p21 and p27 lead to a 35- and 80-fold increase in K(a), respectively, mostly because of a decrease in K(off). At low concentrations, p21 promotes the assembly of active kinase complexes, whereas at higher concentrations, it inhibits activity. Moreover, immunodepletion experiments demonstrate that most of the active cdk4-associated kinase activity also associates with p21. To confirm these results in a natural setting, we examine the assembly of endogenous complexes in mammary epithelial cells after release from a G(0) arrest. In agreement with our other data, cyclin D1 and p21 bind concomitantly to cdk4 during the in vivo assembly of cdk4/cyclin D1 complexes. This complex assembly occurs in parallel to an increase in cyclin D1-associated kinase activity. Immunodepletion experiments demonstrate that most of the cellular cyclin D1-associated kinase activity is also p21 associated. Finally, we find that all three CIP/KIP inhibitors target cdk4 and cyclin D1 to the nucleus. We suggest that in addition to their roles as inhibitors, the p21 family of proteins, originally identified as inhibitors, may also have roles as adaptor proteins that assemble and program kinase complexes for specific functions.
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Low levels of p21 act as an assembly factor for cyclinD/CDK4,6 complex and promote its activation, resulting in cell cycle progression.
“High levels of p21WAF1/CIP1 inhibit the kinase activity of cyclinD/CDK4,6 complexes leading to inhibition of cell cycle progression whereas low levels of p21WAF1/CIP1 act as an assembly factor for cyclinD/CDK4,6 complex and promote its activation resulting in cell cycle progression (Labaer et al., 1997; Welcker et al., 1998; Cheng et al., 1999; Deng et al., 2018).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Labaer et al., 1997
High levels of p21 inhibit kinase activity of cyclinD/CDK4,6 complexes, leading to inhibition of cell cycle progression.
“High levels of p21WAF1/CIP1 inhibit the kinase activity of cyclinD/CDK4,6 complexes leading to inhibition of cell cycle progression whereas low levels of p21WAF1/CIP1 act as an assembly factor for cyclinD/CDK4,6 complex and promote its activation resulting in cell cycle progression (Labaer et al., 1997; Welcker et al., 1998; Cheng et al., 1999; Deng et al., 2018).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Labaer et al., 1997
p21Cip1 and p27Kip1 facilitate cyclin D-CDK assembly and nuclear import without inhibiting CDK4/6 kinase activity.
“Naturally occurring pan-CDK inhibitors, including p21Cip1 and p27Kip1, facilitate cyclin D-CDK assembly and the nuclear import of the resulting complexes without inhibiting CDK4/6 kinase activity (41, 48-51).”
From Targeting CDK4 and CDK6: From Discovery to Therapy (2016) · cites this paper as [48]
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- Authors
- LaBaer, J., Garrett, M. D., Stevenson, L. F., Slingerland, J. M., Sandhu, C., Chou, H. S., Fattaey, A., & Harlow, E.
- Affiliations
- Sunnybrook Health Science Centre (CA)
- Massachusetts General Hospital (US)
- Corresponding author
- LaBaer, J
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1997-04-01
- Volume
- 11
- Issue
- 7
- Pages
- 847-862
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2166529745
- Cited by
- 1,402
- References
- 66
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 20 · 2023: 30 · 2022: 28 · 2021: 27 · 2020: 26 · 2019: 23 · 2018: 23 · 2017: 23 · 2016: 22 · 2015: 36 · 2014: 35 · 2013: 44 · 2012: 32
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massachusetts General Hospital
- National Institutes of Health (7k08ca064166-05)
- National Cancer Institute (CA64166)
- 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
- p21, p27, p57, cyclin-dependent kinase inhibitors, cyclin D1, CDK4, adaptor proteins, kinase activity, mammary epithelial cells, G0 arrest, nuclear targeting, cell cycle regulation
- MeSH terms
- Biological Transport, Breast, Cell Compartmentation, Cell Line, Cell Nucleus, Cell Transformation, Neoplastic, Dose-Response Relationship, Drug, Enzyme Inhibitors, Epithelial Cells, Epithelium, Female, Humans, Microtubule-Associated Proteins, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, Signal Transduction, G1 Phase, Cyclins, Cell Cycle Proteins, Cyclin-Dependent Kinases, Tumor Suppressor Proteins, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase Inhibitor p57, Cyclin-Dependent Kinase 4, Cyclin D
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