ArticleCell death & disease2022
Histone methyltransferase MLL1 drives renal tubular cell apoptosis by p53-dependent repression of E-cadherin during cisplatin-induced acute kidney injury.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 28 citations in OpenAlex.
- Renal IGFBP6 Interacts With THBS1 to Drive Renal Cellular Senescence and Fibrosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- BCG-trained macrophages promote pan-anti-tumor activity through epigenetic rewiring of NOX2-ROS axis.Journal of experimental & clinical cancer research : CR · 2026Article
- Chromatin remodeling and epigenetic regulation in chronic kidney disease.Frontiers in genetics · 2026Review
- The molecular mechanisms and therapeutic potential of p53 in kidney injury repair: a perspective on the p53alpha/delta133p53alpha signaling axis.Renal failure · 2025Review
- Histone methylation of kidney disease: fact or fantasy?Renal failure · 2025Review
- Histone modification-mediated epigenetic regulation in AKI-to-CKD transition: a cell-type-specific perspective.Journal of translational medicine · 2025Review
- Astragaloside IV Alleviates Ulcerative Colitis Progression by Inhibiting WDR5-Mediated ENO1 H3K4me3 Modification.The Kaohsiung journal of medical sciences · 2025Article
- Acute kidney injury: pathogenesis and therapeutic interventions.Molecular biomedicine · 2025Review
- The long non-coding RNA RSDR protects against acute kidney injury in mice by interacting with hnRNPK to regulate DHODH-mediated ferroptosis.Nature communications · 2025Article
- SET8 inhibition preserves PTEN to attenuate kidney cell apoptosis in cisplatin nephrotoxicity.Cell death & disease · 2025Article
- Wdr5-mediated H3K4 methylation facilitates HSPC development via maintenance of genomic stability in zebrafish.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Histone methyltransferase KMT2A promotes pulmonary fibrogenesis via targeting pro-fibrotic factor PU.1 in fibroblasts.Clinical and translational medicine · 2025Article
- TEAD1 Prevents Necroptosis and Inflammation in Cisplatin-Induced Acute Kidney Injury Through Maintaining Mitochondrial Function.International journal of biological sciences · 2025Article
- Enzymatic post-translational modifications of proteins in chronic kidney disease: mechanisms, regulation, and clinical significance.Frontiers in pharmacology · 2025Review
- High Homocysteine-Thiolactone Leads to Reduced MENIN Protein Expression and an Impaired DNA Damage Response: Implications for Neural Tube Defects.Molecular neurobiology · 2024Article
- Inhibition of HDAC8 mitigates AKI by reducing DNA damage and promoting homologous recombination repair.Journal of cellular and molecular medicine · 2024Article
- Lycorine (Lycoris radiata)-a unique natural medicine on breast cancer.Journal of cellular and molecular medicine · 2024Article
- Caffeine and neonatal acute kidney injury.Pediatric nephrology (Berlin, Germany) · 2024Review
- Nucleic acid and protein methylation modification in renal diseases.Acta pharmacologica Sinica · 2024Review
- Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity.Cell death & disease · 2024Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase that interacts with WD repeat domain 5 (WDR5) to regulate cell survival, proliferation, and senescence. The role of MLL1 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we demonstrate that MLL1, WDR5, and trimethylated H3K4 (H3K4me3) were upregulated in renal tubular cells of cisplatin-induced AKI in mice, along with increased phosphorylation of p53 and decreased expression of E-cadherin. Administration of MM102, a selective MLL1/WDR5 complex inhibitor, improved renal function and attenuated tubular injury and apoptosis, while repressing MLL1, WDR5, and H3K4me3, dephosphorylating p53 and preserving E-cadherin. In cultured mouse renal proximal tubular cells (RPTCs) exposed to cisplatin, treatment with MM102 or transfection with siRNAs for either MLL1 or WDR5 also inhibited apoptosis and p53 phosphorylation while preserving E-cadherin expression; p53 inhibition with Pifithrin-α lowered cisplatin-induced apoptosis without affecting expression of MLL1, WDR5, and H3K4me3. Interestingly, silencing of E-cadherin offset MM102's cytoprotective effects, but had no effect on p53 phosphorylation. These findings suggest that MLL1/WDR5 activates p53, which, in turn, represses E-cadherin, leading to apoptosis during cisplatin-induced AKI. Further studies showed that MM102 effectively inhibited cisplatin-triggered DNA damage response (DDR), as indicated by dephosphorylation of ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) proteins, dephosphorylation of checkpoint kinase 1 and 2 (Chk1 and Chk2); depression of γ-H2AX; and restrained cell cycle arrest, as evidenced by decreased expression of p21 and phospho-histone H3 at serine 10 in vitro and in vivo. Overall, we identify MLL1 as a novel DDR regulator that drives cisplatin-induced RPTC apoptosis and AKI by modulating the MLL1/WDR5-/ATR/ATM-Chk-p53-E-cadherin axis. Targeting the MLL1/WDR5 complex may have a therapeutic potential for the treatment of AKI.
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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 Socratic graph.