ArticleThe Journal of biological chemistry2020
TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 16 citations in OpenAlex.
- HIF-3α/PPAR-γ Regulates Hypoxia Tolerance by Altering Glycolysis and Lipid Synthesis in Blunt Snout Bream (International journal of molecular sciences · 2025Article
- Melanoma-derived extracellular vesicles transfer proangiogenic factors.Oncology research · 2025Review
- TET3-overexpressing macrophages promote endometriosis.The Journal of clinical investigation · 2024Article
- Recent Advances and Therapeutic Implications of 2-Oxoglutarate-Dependent Dioxygenases in Ischemic Stroke.Molecular neurobiology · 2024Review
- Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3.Nature communications · 2024Article
- Oxygen-regulated post-translation modifications as master signalling pathway in cells.EMBO reports · 2023Review
- Tumor hypoxia: From basic knowledge to therapeutic implications.Seminars in cancer biology · 2023Review
- Physioxia-induced downregulation of Tet2 in hematopoietic stem cells contributes to enhanced self-renewal.Blood · 2022Article
- Analysis of genome and methylation changes in Chinese indigenous chickens over time provides insight into species conservation.Communications biology · 2022Article
- Epigenetic and post-transcriptional repression support metabolic suppression in chronically hypoxic goldfish.Scientific reports · 2022Article
- Role of prolyl hydroxylase domain proteins in bone metabolism.Osteoporosis and sarcopenia · 2022Review
- The roles of inducible chromatin and transcriptional memory in cellular defense system responses to redox-active pollutants.Free radical biology & medicine · 2021Review
- Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: Triggering a Lethal Fight to Keep Control of the Ten-Eleven Translocase (TET)-Associated DNA Demethylation?Pathogens (Basel, Switzerland) · 2020Review
- Hypoxic Regulation of Gene Transcription and Chromatin: Cause and Effect.International journal of molecular sciences · 2020Review
- Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression.International journal of molecular sciences · 2020Review
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypoxia-inducible factors are heterodimeric transcription factors that play a crucial role in a cell's ability to adapt to low oxygen. The von Hippel-Lindau tumor suppressor (pVHL) acts as a master regulator of HIF activity, and its targeting of prolyl hydroxylated HIF-α for proteasomal degradation under normoxia is thought to be a major mechanism for pVHL tumor suppression and cellular response to oxygen. Whether pVHL regulates other targets through a similar mechanism is largely unknown. Here, we identify TET2/3 as novel targets of pVHL. pVHL induces proteasomal degradation of TET2/3, resulting in reduced global 5-hydroxymethylcytosine levels. Conserved proline residues within the LAP/LAP-like motifs of these two proteins are hydroxylated by the prolyl hydroxylase enzymes (PHD2/EGLN1 and PHD3/EGLN3), which is prerequisite for pVHL-mediated degradation. Using zebrafish as a model, we determined that global 5-hydroxymethylcytosine levels are enhanced in vhl-null, egln1a/b-double-null, and egln3-null embryos. Therefore, we reveal a novel function for the PHD-pVHL pathway in regulating TET protein stability and activity. These data extend our understanding of how TET proteins are regulated and provide new insight into the mechanisms of pVHL in tumor suppression.
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