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CDK inhibitors: positive and negative regulators of G1-phase progression
Open accessAbstract
Mitogen-dependent progression through the first gap phase (G1) and initiation of DNA synthesis (S phase) during the mammalian cell division cycle are cooperatively regulated by several classes of cyclin-dependent kinases (CDKs) whose activities are in turn constrained by CDK inhibitors (CKIs). CKIs that govern these events have been assigned to one of two families based on their structures and CDK targets. The first class includes the INK4 proteins (inhibitors of CDK4), so named for their ability to specifically inhibit the catalytic subunits of CDK4 and CDK6. Four such proteins [p16 (Serrano et al. 1993), p15 (Hannon and Beach 1994), p18 (Guan et al. 1994; Hirai et al. 1995), and p19 (Chan et al. 1995; Hirai et al. 1995)] are composed of multiple ankyrin repeats and bind only to CDK4 and CDK6 but not to other CDKs or to D-type cyclins. The INK4 proteins can be contrasted with more broadly acting inhibitors of the Cip/Kip family whose actions affect the activities of cyclin D-, E-, and A-dependent kinases. The latter class includes p21 (Gu et al. 1993; Harper et al. 1993; El-Deiry et al. 1993; Xiong et al. 1993a; Dulic et al. 1994; Noda et al. 1994), p27 (Polyak et al. 1994a,b; Toyoshima and Hunter 1994), and p57 (Lee et al. 1995; Matsuoka et al. 1995), all of which contain characteristic motifs within their amino-terminal moieties that enable them to bind both to cyclin and CDK subunits (Chen et al. 1995, 1996; Nakanishi et al. 1995; Warbrick et al. 1995; Lin et al. 1996; Russo et al. 1996). Based largely on in vitro experiments and in vivo overexpression studies, CKIs of the Cip/Kip family were initially thought to interfere with the activities of cyclin D-, E-, and A-dependent kinases. More recent work has altered this view and revealed that although the Cip/Kip proteins are potent inhibitors of cyclin Eand A-dependent CDK2, they act as positive regulators of cyclin Ddependent kinases. This challenges previous assumptions about how the G1/S transition of the mammalian cell cycle is governed, helps explain some enigmatic features of cell cycle control that also involve the functions of the retinoblastoma protein (Rb) and the INK4 proteins, and changes our thinking about how either p16 loss or overexpression of cyclin D-dependent kinases contribute to cancer. Here we focus on the biochemical interactions that occur between CKIs and cyclin Dand E-dependent kinases in cultured mammalian cells, emphasizing the manner by which different positive and negative regulators of the cell division cycle cooperate to govern the G1-to-S transition. To gain a more comprehensive understanding of the biology of CDK inhibitors, readers are encouraged to refer to a rapidly emerging but already extensive literature (for review, see Elledge and Harper 1994; Sherr and Roberts 1995; Chellappan et al. 1998; Hengst and Reed 1998a; Kiyokawa and Koff 1998; Nakayama 1998; Ruas and Peters 1998).
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“In contrast, we found that incubation of AHPs with IL-1β induces a dramatic decline in levels of cyclin D1, a cell cycle regulatory protein that controls specific cyclin-dependent kinases such as cdk4 (31).”
From IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress (2008) · cites this paper as [31]
In the citing paper
“Due to the critical regulatory role of these cell cycle factors, senescence signaling typically acts by decreasing cyclin–CDK activity or increasing CDK inhibitor levels.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [34]
In the citing paper
“CDK4/6 activity bridges numerous extracellular signaling pathways to the cell cycle (Sherr and Roberts, 1999).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Sherr and Roberts, 1999
In the citing paper
“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 [41]
In the citing paper
“In many cell types, transcription of CCND1 and cyclin D1 assembly with CDK4 each depend on activation of a RAS-dependent kinase cascade that relies on the sequential activities of RAF1, MEK1 and MEK2, and ERKs (39-42).”
From Targeting CDK4 and CDK6: From Discovery to Therapy (2016) · cites this paper as [41]
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“, 2004), which prevents cell cycle progression from the G1 to S phases by inhibiting two cycle-dependent kinases, CDK4 and CDK6 (Sherr and Roberts, 1999).”
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Metadata
- Authors
- Sherr, C. J., & Roberts, J. M.
- Affiliations
- St. Jude Children's Research Hospital (US)
- ORCID
- Sherr, C. J.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-06-15
- Volume
- 13
- Issue
- 12
- Pages
- 1501-1512
- ISSN
- 0890-9369 (ISSN-L)
- OpenAlex
- W2121619780
- Cited by
- 6,115
- References
- 151
- Citations by year
- 2026: 71 · 2025: 97 · 2024: 94 · 2023: 122 · 2022: 137 · 2021: 148 · 2020: 149 · 2019: 142 · 2018: 146 · 2017: 160 · 2016: 154 · 2015: 208 · 2014: 207 · 2013: 234 · 2012: 255
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- cyclin-dependent kinase inhibitors, cyclin-dependent kinases, G1 phase progression, cell cycle regulation, p16, p21, p27, p57, CDK4, CDK6, cyclin D, cyclin E, cyclin A, ankyrin repeats, cell cycle checkpoint control, tumor suppressor
- MeSH terms
- Animals, Carrier Proteins, Catalysis, Cell Cycle, Enzyme Inhibitors, Humans, Microtubule-Associated Proteins, Neoplasms, G1 Phase, Cyclins, Cell Cycle Proteins, Cyclin-Dependent Kinases, Cyclin E, Cyclin-Dependent Kinase Inhibitor p16, Holoenzymes, Tumor Suppressor Proteins, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase Inhibitor p19, Cyclin D
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