ArticleToxicology and applied pharmacology2013
p53 activation by Ni(II) is a HIF-1α independent response causing caspases 9/3-mediated apoptosis in human lung cells.
Article in Toxicology and applied pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 35 citations in OpenAlex.
- The role of hypoxia-inducible factor 1 alpha (HIF-1α) modulation in heavy metal toxicity.Archives of toxicology · 2023Review
- Vulnerability of HIF1α and HIF2α to damage by proteotoxic stressors.Toxicology and applied pharmacology · 2022Article
- NADCell cycle (Georgetown, Tex.) · 2021Article
- Chemical hypoxia induces apoptosis of human pluripotent stem cells by a NOXA-mediated HIF-1α and HIF-2α independent mechanism.Scientific reports · 2020Article
- Toxicological Antagonism among Welding Fume Metals: Inactivation of Soluble Cr(VI) by Iron.Chemical research in toxicology · 2018Article
- Serum Se, Ni, and As are associated with HPV infection and CIN2+ among Uyghur women in rural China.BMC cancer · 2018Article
- Role of Hypoxia-Inducible Factors 1α (HIF1α) in SH-SY5Y Cell Autophagy Induced by Oxygen-Glucose Deprivation.Medical science monitor : international medical journal of experimental and clinical research · 2018Article
- Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells.Toxicology and applied pharmacology · 2017Article
- 20S immunoproteasomes remove formaldehyde-damaged cytoplasmic proteins suppressing caspase-independent cell death.Scientific reports · 2017Article
- Immunoproteomic identification and characterization of NiCell death & disease · 2017Article
- Formaldehyde Is a Potent Proteotoxic Stressor Causing Rapid Heat Shock Transcription Factor 1 Activation and Lys48-Linked Polyubiquitination of Proteins.The American journal of pathology · 2016Article
- Proteomic Assessment of Biochemical Pathways That Are Critical to Nickel-Induced Toxicity Responses in Human Epithelial Cells.PloS one · 2016Article
- Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics.Environmental health perspectives · 2016Article
- Metallothionein 2A core promoter region genetic polymorphism and its impact on the risk, tumor behavior, and recurrences of sinonasal inverted papilloma (Schneiderian papilloma).Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
- Toxicogenomic effect of nickel and beyond.Archives of toxicology · 2014Review
- Metallic nickel nanoparticles may exhibit higher carcinogenic potential than fine particles in JB6 cells.PloS one · 2014Article
- Uptake, p53 pathway activation, and cytotoxic responses for Co(II) and Ni(II) in human lung cells: implications for carcinogenicity.Toxicological sciences : an official journal of the Society of Toxicology · 2013Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Hypoxia mimic nickel(II) is a human respiratory carcinogen with a suspected epigenetic mode of action. We examined whether Ni(II) elicits a toxicologically significant activation of the tumor suppressor p53, which is typically associated with genotoxic responses. We found that treatments of H460 human lung epithelial cells with NiCl2 caused activating phosphorylation at p53-Ser15, accumulation of p53 protein and depletion of its inhibitor MDM4 (HDMX). Confirming the activation of p53, its knockdown suppressed the ability of Ni(II) to upregulate MDM2 and p21 (CDKN1A). Unlike DNA damage, induction of GADD45A by Ni(II) was p53-independent. Ni(II) also increased p53-Ser15 phosphorylation and p21 expression in normal human lung fibroblasts. Although Ni(II)-induced stabilization of HIF-1α occurred earlier, it had no effect on p53 accumulation and Ser15 phosphorylation. Ni(II)-treated H460 cells showed no evidence of necrosis and their apoptosis and clonogenic death were suppressed by p53 knockdown. The apoptotic role of p53 involved a transcription-dependent program triggering the initiator caspase 9 and its downstream executioner caspase 3. Two most prominently upregulated proapoptotic genes by Ni(II) were PUMA and NOXA but only PUMA induction required p53. Knockdown of p53 also led to derepression of antiapoptotic MCL1 in Ni(II)-treated cells. Overall, our results indicate that p53 plays a major role in apoptotic death of human lung cells by Ni(II). Chronic exposure to Ni(II) may promote selection of resistant cells with inactivated p53, providing an explanation for the origin of p53 mutations by this epigenetic carcinogen.
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