ArticleMolecular brain2015
Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1/CIP1) expression.
Article in Molecular brain, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 59 citations in OpenAlex.
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- PF-06447475 Molecule Attenuates the Neuropathology of Familial Alzheimer's and Coexistent Parkinson's Disease Markers in PSEN1 I416T Dopaminergic-like Neurons.Molecules (Basel, Switzerland) · 2025Article
- The Multifaceted Role of LRRK2 in Parkinson's Disease.Brain sciences · 2025Review
- Aging, cellular senescence and Parkinson's disease.Journal of Parkinson's disease · 2025Review
- Dysregulated LINC01133 expression in laryngeal carcinoma: Prognostic implications and predicted ceRNA interactome.Molecular biology research communications · 2025Article
- Leucine-rich repeat kinase 2 at a glance.Journal of cell science · 2023Article
- Rotenone Blocks the Glucocerebrosidase Enzyme and Induces the Accumulation of Lysosomes and Autophagolysosomes Independently of LRRK2 Kinase in HEK-293 Cells.International journal of molecular sciences · 2023Article
- LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis.International journal of molecular sciences · 2023Article
- Maintaining Genome Integrity: Protein Kinases and Phosphatases Orchestrate the Balancing Act of DNA Double-Strand Breaks Repair in Cancer.International journal of molecular sciences · 2023Review
- Targeting Mitochondria as a Therapeutic Approach for Parkinson's Disease.Cellular and molecular neurobiology · 2023Review
- Nuclear α-Synuclein-Derived Cytotoxic Effect via Altered Ribosomal RNA Processing in Primary Mouse Embryonic Fibroblasts.International journal of molecular sciences · 2023Article
- Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53.Frontiers in molecular biosciences · 2022Review
- Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration.Antioxidants (Basel, Switzerland) · 2021Review
- LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells.Oxidative medicine and cellular longevity · 2021Article
- Article
- Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways.International journal of molecular sciences · 2020Article
- Down-Regulation of miR-23a-3p Mediates Irradiation-Induced Neuronal Apoptosis.International journal of molecular sciences · 2020Article
- G2019s LRRK2 promotes mitochondrial fission and increases TNFα-mediated neuroinflammation responses.Animal cells and systems · 2019Article
- Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein.Cell cycle (Georgetown, Tex.) · 2019Article
- Significant and Durable Clinical Response to Sorafenib and Radiation Therapy for a Patient With Stage IV Hepatocellular Carcinoma andJCO precision oncology · 2019Article
Corrections and comments
- Erratum issued
Authors and funding
11 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLeucine-rich repeat kinase 2 (LRRK2) is a gene in which a mutation causes Parkinson's disease (PD), and p53 is a prototype tumor suppressor. In addition, activation of p53 in patient with PD has been reported by several studies. Because phosphorylation of p53 is critical for regulating its activity and LRRK2 is a kinase, we tested whether p53 is phosphorylated by LRRK2.
resultsLRRK2 phosphorylates threonine (Thr) at TXR sites in an in vitro kinase assay, and the T304 and T377 were identified as putative phosphorylated residues. An increase of phospho-Thr in the p53 TXR motif was confirmed in the cells overexpressing G2019S, and human induced pluripotent stem (iPS) cells of a G2019S carrier. Interactions between LRRK2 and p53 were confirmed by co-immunoprecipitation of lysates of differentiated SH-SY5Y cells. LRRK2 mediated p53 phosphorylation translocalizes p53 predominantly to nucleus and increases p21(WAF1/CIP1) expression in SH-SY5Y cells based on reverse transcription-polymerase chain reaction and Western blot assay results. The luciferase assay using the p21(WAF1/CIP1) promoter-reporter also confirmed that LRRK2 kinase activity increases p21 expression. Exogenous expression of G2019S and the phosphomimetic p53 T304/377D mutants increased expression of p21(WAF1/CIP1) and cleaved PARP, and cytotoxicity in the same cells. We also observed increase of p21 expression in rat primary neuron cells after transient expression of p53 T304/377D mutants and the mid-brain lysates of the G2019S transgenic mice.
conclusionp53 is a LRRK2 kinase substrate. Phosphorylation of p53 by LRRK2 induces p21(WAF1/CIP1) expression and apoptosis in differentiated SH-SY5Y cells and rat primary neurons.
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