{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Haggerty NR"],"funding":["NIEHS NIH HHS"],"pagination":["110707"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12596596"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["301(11)"],"pubmed_abstract":["The primary mechanism that controls manganese (Mn) homeostasis in mammals is the activation of hypoxia-inducible factor (HIF) transcription factors by elevated Mn, which transcriptionally upregulates expression of the Mn efflux transporter SLC30A10 to reduce cellular/organismal Mn levels. Here, we identify an additional unexpected component of the Mn-induced and HIF-dependent homeostatic response that represses SLC30A10 expression. In cells, (1) Mn treatment upregulated expression of the transcription factor NR4A1 (also called Nur77); (2) NR4A1 knockdown increased SLC30A10 expression and reduced the sensitivity of wildtype, but not ΔSLC30A10, cells to Mn toxicity; and (3) overexpression of NR4A1 reduced SLC30A10 expression and increased sensitivity to Mn toxicity. Thus, NR4A1 is a Mn-respo"],"journal":["The Journal of biological chemistry"],"pubmed_title":["NR4A1 is a HIF-dependent repressor of SLC30A10 transcription that controls manganese homeostasis."],"pmcid":["PMC12596596"],"funding_grant_id":["R01 ES031574","R01 ES024812"],"pubmed_authors":["Sharma N","Lee YR","Smith DR","Haggerty NR","Jursa T","Mukhopadhyay S"],"additional_accession":[]},"is_claimable":false,"name":"NR4A1 is a HIF-dependent repressor of SLC30A10 transcription that controls manganese homeostasis.","description":"The primary mechanism that controls manganese (Mn) homeostasis in mammals is the activation of hypoxia-inducible factor (HIF) transcription factors by elevated Mn, which transcriptionally upregulates expression of the Mn efflux transporter SLC30A10 to reduce cellular/organismal Mn levels. Here, we identify an additional unexpected component of the Mn-induced and HIF-dependent homeostatic response that represses SLC30A10 expression. In cells, (1) Mn treatment upregulated expression of the transcription factor NR4A1 (also called Nur77); (2) NR4A1 knockdown increased SLC30A10 expression and reduced the sensitivity of wildtype, but not ΔSLC30A10, cells to Mn toxicity; and (3) overexpression of NR4A1 reduced SLC30A10 expression and increased sensitivity to Mn toxicity. Thus, NR4A1 is a Mn-respo","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-05T13:04:09.598Z","creation":"2026-05-17T03:13:23.965Z"},"accession":"S-EPMC12596596","cross_references":{"pubmed":["40945722"],"doi":["10.1016/j.jbc.2025.110707"]}}