{"id":"4346d9b7-7c5e-5c20-8c2b-f2f7b73d8437","stable_key":"488ea171-36b8-5ef6-b5d3-98563980fdbf:hbot-phd2-oxygen-sensor","predicate":"destabilises","statement":"Silencing PHD2 alone was sufficient to stabilise and activate HIF-1alpha in normoxia in every human cell type investigated, while silencing PHD1 or PHD3 had no effect on HIF-1alpha stability, making PHD2 the critical oxygen sensor setting the low steady-state level of HIF-1alpha.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"45da75d9-6cb4-54c4-98ba-a20e96d686cb","mechanism_event_label":"One enzyme is the thermostat: it destroys the low-oxygen signal whenever oxygen is present.","subject":{"id":"8681acd7-4f56-59e0-a757-37b8376c8bde","slug":"egln1","display_name":"EGLN1 / PHD2","entity_type_key":"protein"},"object":{"id":"22b3e241-94b0-55fd-a233-c63af92520d8","slug":"hif1a","display_name":"HIF-1 alpha","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"45da75d9-6cb4-54c4-98ba-a20e96d686cb","stable_key":"488ea171-36b8-5ef6-b5d3-98563980fdbf:hbot-phd2-oxygen-sensor-event","event_type":"biochemical_relationship","label":"One enzyme is the thermostat: it destroys the low-oxygen signal whenever oxygen is present.","description":"Silencing PHD2 alone was sufficient to stabilise and activate HIF-1alpha in normoxia in every human cell type investigated, while silencing PHD1 or PHD3 had no effect on HIF-1alpha stability, making PHD2 the critical oxygen sensor setting the low steady-state level of HIF-1alpha.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"4a5eb867-fe65-5ebc-83d8-38bf855eb498","slug":"phd2-silenced-cells","display_name":"Human cells with PHD2 silenced by short interfering RNA","entity_type_key":"protein_state"},"role":"tested_state","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"1c3b5bb5-6162-5846-ad80-b5a1af988816","slug":"phd2-hydroxylation-of-hif1a","display_name":"PHD2-catalysed prolyl hydroxylation of HIF-1alpha","entity_type_key":"cellular_process"},"role":"catalysed_reaction","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c98e377e-3def-5e82-b850-f576372096d4","slug":"hif1a-proline-residues","display_name":"The hydroxylated proline residues of HIF-1alpha","entity_type_key":"protein_state"},"role":"modified_site","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"8681acd7-4f56-59e0-a757-37b8376c8bde","slug":"egln1","display_name":"EGLN1 / PHD2","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"22b3e241-94b0-55fd-a233-c63af92520d8","slug":"hif1a","display_name":"HIF-1 alpha","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/hbot-research/12912907.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"db0613321b1804356dbb60637bba0616eaaaeab041f63a095ecfcaeac3ec780e\", \"start_char\": 0, \"end_char\": 1190, \"text_sha256\": \"db0613321b1804356dbb60637bba0616eaaaeab041f63a095ecfcaeac3ec780e\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Short interfering RNA silencing of each HIF prolyl-hydroxylase in human cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"PHD1, PHD2 and PHD3 silencing in normoxia and after brief hypoxia","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A silencing study assigning distinct roles. It establishes which isoform sets the resting level, not the oxygen concentration at which each acts.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake.","comparator":null,"unit":null,"notes":"","entity":{"slug":"hyperbaric-oxygen","display_name":"Hyperbaric oxygen therapy","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"One enzyme is the thermostat: it destroys the low-oxygen signal whenever oxygen is present.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[hbot-p12912907] HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. (2003). https://pubmed.ncbi.nlm.nih.gov/12912907/ DOI: 10.1093/emboj/cdg392","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Cytosol","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"e3007e51-2438-5e7a-a75b-1e1f1768c0b7","evidence_kind":"source_excerpt","locator":"Lines 933-944","start_line":933,"end_line":944,"excerpt":"### hbot-phd2-oxygen-sensor\nSilencing PHD2 alone was sufficient to stabilise and activate HIF-1alpha in normoxia in every human cell type investigated, while silencing PHD1 or PHD3 had no effect on HIF-1alpha stability, making PHD2 the critical oxygen sensor setting the low steady-state level of HIF-1alpha.\nCondition category: normal\nnutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake.\nplain_language: One enzyme is the thermostat: it destroys the low-oxygen signal whenever oxygen is present.\norganism: Human cells\ntissue_or_cell_type: Cytosol\nexperimental_model: Short interfering RNA silencing of each HIF prolyl-hydroxylase in human cells\nlimitations: A silencing study assigning distinct roles. It establishes which isoform sets the resting level, not the oxygen concentration at which each acts.\nexposure: PHD1, PHD2 and PHD3 silencing in normoxia and after brief hypoxia\nevidence_span: {\"source_cache\": \"artifacts/hbot-research/12912907.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"db0613321b1804356dbb60637bba0616eaaaeab041f63a095ecfcaeac3ec780e\", \"start_char\": 0, \"end_char\": 1190, \"text_sha256\": \"db0613321b1804356dbb60637bba0616eaaaeab041f63a095ecfcaeac3ec780e\"}\n[hbot-p12912907] HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. (2003). https://pubmed.ncbi.nlm.nih.gov/12912907/ DOI: 10.1093/emboj/cdg392","model_system":"Short interfering RNA silencing of each HIF prolyl-hydroxylase in human cells","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [hbot-p12912907] HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. (2003). https://pubmed.ncbi.nlm.nih.gov/12912907/ DOI: 10.1093/emboj/cdg392","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"dbf39b48-c95e-5291-b404-349ffbc4488f","stable_key":"import-488ea171-36b8-5ef6-b5d3-98563980fdbf","title":"Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"fb2443321804010d82c6b96ab61cc51b4b6628ddbb15751cb0e90b491606e79c","revision_id":"bb699ea5-b492-5728-b22c-48f0842a8ac9","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}