Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex
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Neurons that reenter a cell cycle after maturation are at increased risk for death, yet the mechanisms by which a normal neuron suppresses the cycle remain mostly unknown. Our laboratory has shown that cyclin-dependent kinase 5 (Cdk5) is a potent cell cycle suppressor, and we report here on the molecular basis of this activity. Cell cycle suppression by Cdk5 requires its binding to the p35 activator protein. The related p39 and p25 proteins cannot serve as substitutes. Unexpectedly, Cdk5 enzymatic activity is not required to perform this function. Rather, the link to cell cycle regulation is made through the formation of a previously unknown complex consisting of the p35–Cdk5 dimer and E2F1. Formation of this complex excludes the E2F1 cofactor, DP1, thus inhibiting E2F1 binding to the promoters of various cell cycle genes. This anti-cell cycle activity is most likely a neuroprotective function of Cdk5.
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Cdk5 nuclear localization relies on its interaction with p27, and its cell-cycle suppression activity is achieved by direct binding to E2F1, blocking E2F1 access to DNA and avoiding transcription of cell-cycle progression genes.
“Studies have proposed that Cdk5 nuclear localization relies on its interaction with p27, and its cell-cycle suppression activity is achieved by direct binding to E2F1, blocking the access of E2F1 to the DNA and thus avoiding the transcription of genes responsible for cell-cycle progression [103], [104].”
From Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease (2014) · cites this paper as [103]
Cdk5 has a crucial role as a cell-cycle suppressor in post-mitotic neurons.
“recent data have suggested a crucial role for Cdk5 as a cell-cycle suppressor in post-mitotic neurons.”
From Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease (2014) · cites this paper as [103]
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Cyclin-dependent kinases in neurodegenerative disorders
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- Authors
- Zhang, J., Li, H., Yabut, O., Fitzpatrick, H., D'Arcangelo, G., & Herrup, K.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Herrup, Karl
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-04-14
- Volume
- 30
- Issue
- 15
- Pages
- 5219-5228
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2862267
- OpenAlex
- W2046640720
- Cited by
- 96
- References
- 47
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 9 · 2019: 1 · 2018: 6 · 2017: 4 · 2016: 3 · 2015: 11 · 2014: 6 · 2013: 5 · 2012: 17
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS020591, NS20591)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- cyclin-dependent kinase 5, E2F1, DP1, p35, p39, p25, neuroprotection, postmitotic neurons, transcriptional repression
- MeSH terms
- Animals, Brain, Cell Cycle, Cell Nucleus, Cells, Cultured, Cytoplasm, DNA, Mice, Inbred C57BL, Mice, Transgenic, Models, Neurological, Nerve Tissue Proteins, Neurons, Phosphotransferases, Cell Line, Tumor, Transcription Factor DP1, E2F1 Transcription Factor, Cyclin-Dependent Kinase 5, Mice
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