ArticleCell death & disease2019
Site-specific phosphorylation of Fbxw7 by Cdk5/p25 and its resulting decreased stability are linked to glutamate-induced excitotoxicity.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Calpain Inhibitors as Potential Therapeutic Modulators in Neurodegenerative Diseases.Neurochemical research · 2022Pooled it
- Expanding clinical variability in FBXW7-related neurodevelopmental disorder: a multicenter case series.Journal of neurodevelopmental disorders · 2026Article
- FBXW7-Related Neurodevelopmental Disorder: Clinical Spectrum, Molecular Mechanisms, and Tumor Predisposition.Human mutation · 2026Review
- CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer's disease.Translational psychiatry · 2025Article
- FBXW7 in gastrointestinal cancers: from molecular mechanisms to therapeutic prospects.Frontiers in pharmacology · 2024Review
- Anti-apoptosis effect of traditional Chinese medicine in the treatment of cerebral ischemia-reperfusion injury.Apoptosis : an international journal on programmed cell death · 2023Review
- FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2.Cell death & disease · 2023Article
- RNAseq Analysis of FABP4 Knockout Mouse Hippocampal Transcriptome Suggests a Role for WNT/β-Catenin in Preventing Obesity-Induced Cognitive Impairment.International journal of molecular sciences · 2023Article
- Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.American journal of human genetics · 2022Article
- Clinical significance of FBXW7 loss of function in human cancers.Molecular cancer · 2022Review
- Role of cyclin-dependent kinase 5 in early brain injury following experimental subarachnoid hemorrhage.Experimental and therapeutic medicine · 2022Article
- The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease.International journal of molecular sciences · 2021Review
- Hippocampal CA3 transcriptional modules associated with granule cell alterations and cognitive impairment in refractory mesial temporal lobe epilepsy patients.Scientific reports · 2021Article
- Phosphorylation-dependent subfunctionalization of the calcium-dependent protein kinase CPK28.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Implications of FBXW7 in Neurodevelopment and Neurodegeneration: Molecular Mechanisms and Therapeutic Potential.Frontiers in cellular neuroscience · 2021Review
- Review
- Excitotoxicity: Still Hammering the Ischemic Brain in 2020.Frontiers in neuroscience · 2020Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase that regulates brain development and neurodegeneration. Cdk5 is activated by p25 that is generated from calpain-dependent cleavage of p35. The generation of p25 is responsible for the aberrant hyper-activation of Cdk5, which causes neurodegeneration. Using in vitro assays, we discovered that F-box/WD repeat-containing protein 7 (Fbxw7) is a new substrate of Cdk5. Additionally, Cdk5-dependent phosphorylation of Fbxw7 was detected in the presence of p25, and two amino acid residues (S349 and S372) were determined to be major phosphorylation sites. This phosphorylation was eventually linked to decreased stability of Fbxw7. Using a culture model of cortical neurons challenged with glutamate, we confirmed that decreased stability of Fbxw7 was indeed Cdk5-dependent. Furthermore, diminished levels of Fbxw7 led to increased levels of transcription factor AP-1 (c-Jun), a known substrate of Fbxw7. Given that previous reports demonstrate that c-Jun plays a role in accelerating neuronal apoptosis in these pathological models, our data support the concepts of a molecular cascade in which Cdk5-mediated phosphorylation of Fbxw7 negatively regulates Fbxw7 expression, thereby contributing to neuronal cell death following glutamate-mediated excitotoxicity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.