ArticleScientific reports2015
Cdk5-mediated inhibition of APC/C-Cdh1 switches on the cyclin D1-Cdk4-pRb pathway causing aberrant S-phase entry of postmitotic neurons.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 33 citations in OpenAlex.
- Deficiency of Parkinson's Related Protein DJ-1 Alters Cdk5 Signalling and Induces Neuronal Death by Aberrant Cell Cycle Re-entry.Cellular and molecular neurobiology · 2023Article
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
- Article
- Amyloid-β Induces Cdh1-Mediated Rock2 Stabilization Causing Neurodegeneration.Frontiers in pharmacology · 2022Article
- APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer's disease.Frontiers in pharmacology · 2022Review
- Review
- Refocusing the Brain: New Approaches in Neuroprotection Against Ischemic Injury.Neurochemical research · 2021Review
- Core cell cycle machinery is crucially involved in both life and death of post-mitotic neurons.Cellular and molecular life sciences : CMLS · 2020Review
- Site-specific phosphorylation of Fbxw7 by Cdk5/p25 and its resulting decreased stability are linked to glutamate-induced excitotoxicity.Cell death & disease · 2019Article
- Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CMolecular cancer research : MCR · 2019Article
- Primary neurons can enter M-phase.Scientific reports · 2019Article
- Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy.Oncotarget · 2018Article
- CDK5-dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons.Traffic (Copenhagen, Denmark) · 2017Article
- Cdk5 links with DNA damage response and cancer.Molecular cancer · 2017Review
- Upregulation of Cdh1 Attenuates Isoflurane-Induced Neuronal Apoptosis and Long-Term Cognitive Impairments in Developing Rats.Frontiers in cellular neuroscience · 2017Article
- Taming the Beast: Control of APC/CCold Spring Harbor symposia on quantitative biology · 2017Article
- O-GlcNAcylation Antagonizes Phosphorylation of CDH1 (CDC20 Homologue 1).The Journal of biological chemistry · 2016Article
- A decade of the anaphase-promoting complex in the nervous system.Genes & development · 2016Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that regulates cell cycle progression in proliferating cells. To enter the S-phase, APC/C must be inactivated by phosphorylation of its cofactor, Cdh1. In post-mitotic cells such as neurons APC/C-Cdh1 complex is highly active and responsible for the continuous degradation of mitotic cyclins. However, the specific molecular pathway that determines neuronal cell cycle blockade in post-mitotic neurons is unknown. Here, we show that activation of glutamatergic receptors in rat cortical primary neurons endogenously triggers cyclin-dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1 leading to its cytoplasmic accumulation and disassembly from the APC3 core protein, causing APC/C inactivation. Conversely, pharmacological or genetic inhibition of Cdk5 promotes Cdh1 ubiquitination and proteasomal degradation. Furthermore, we show that Cdk5-mediated phosphorylation and inactivation of Cdh1 leads to p27 depletion, which switches on the cyclin D1-cyclin-dependent kinase-4 (Cdk4)-retinoblastoma protein (pRb) pathway to allow the S-phase entry of neurons. However, neurons do not proceed through the cell cycle and die by apoptosis. These results indicate that APC/C-Cdh1 actively suppresses an aberrant cell cycle entry and death of neurons, highlighting its critical function in neuroprotection.
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