ArticleThe Journal of biological chemistry2014
Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 83 citations in OpenAlex.
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- Metals and Metallothionein Expression in Relation to Progression of Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka.Diseases (Basel, Switzerland) · 2022Article
- Thymoquinone Induces Nrf2 Mediated Adaptive Homeostasis: Implication for Mercuric Chloride-Induced Nephrotoxicity.ACS omega · 2022Article
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- Zinc Acetate Dihydrate Tablet-Associated Gastritis Occurring in a Post-Hematopoietic Stem Cell Transplant Recipient.Case reports in gastrointestinal medicine · 2022Article
- Single-cell RNA sequencing in vision research: Insights into human retinal health and disease.Progress in retinal and eye research · 2021Review
- Are granulins copper sequestering proteins?Proteins · 2021Article
- Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells.Experimental and therapeutic medicine · 2021Article
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Induction of metallothionein (MT) expression is involved in metal homeostasis and detoxification. To identify the key pathways that regulate metal-induced cytotoxicity, we investigate how phosphorylated metal-responsive transcription factor-1 (MTF-1) contributed to induction of MT expression. Immortal human embryonic kidney cells (HEK cells) were treated with seven kinds of metals including cadmium chloride (CdCl2), zinc sulfate (ZnSO4), copper sulfate(CuSO4), lead acetate (PbAc), nickel sulfate (NiSO4), sodium arsenite (NaAsO2), and potassium bichromate (K2Cr2O7). The MT expression was induced in a dose-response and time-dependent manner upon various metal treatments. A cycle of phosphorylation and dephosphorylation was required for translocation of MTF-1 from cytoplasm to nucleus, leading to the up-regulation of MTs expression. Protein phosphatase 2A (PP2A) participated in regulating MT expression through dephosphorylation of MTF-1. A loss-of-function screen revealed that the specific PP2A complexes containing PR110 were involved in metal-induced MT expression. Suppression of PP2A PR110 in HEK cells resulted in the persistent MTF-1 phosphorylation and the disturbance of MTF-1 nuclear translocation, which was concomitant with a significant decrease of MT expression and enhanced cytotoxicity in HEK cells. Notably, MTF-1 was found in complex with specific PP2A complexes containing the PR110 subunit upon metal exposure. Furthermore, we identify that the dephosphorylation of MTF-1 at residue Thr-254 is directly regulated by PP2A PR110 complexes and responsible for MTF-1 activation. Taken together, these findings delineate a novel pathway that determines cytotoxicity in response to metal treatments and provide new insight into the role of PP2A in cellular stress response.
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