{"doi":"10.1101/2020.10.28.359018","title":"Cycling hypoxia selects for constitutive HIF stabilization","abstract":"Abstract Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF-α stabilization becomes constitutive even under normoxia, a condition known as pseudohypoxia . Herein, we develop a mathematical model that predicts the effects of fluctuating levels of oxygen availability on stabilization of HIF-α and its client proteins based on fitness. The model shows that facultative regulation of HIF-α always promotes greater cell fitness than constitutive regulation. However, cell fitness is nearly identical regardless of HIF-α regulation strategy when there are rapid periodic fluctuations in oxygenation. Furthermore, the model predicts that stochastic changes in oxygenation favor facultative HIF-α regulation. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127574,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":280731,"name":"Jill Gallaher","orcid":"0000-0001-9831-6676","position":1,"is_corresponding":false},{"id":294827,"name":"Joel S. Brown","orcid":"0000-0002-0958-9494","position":2,"is_corresponding":false},{"id":432809,"name":"Michal R. Tomaszewski","orcid":"0000-0002-3194-9492","position":3,"is_corresponding":false},{"id":577864,"name":"Punit Borad","orcid":null,"position":4,"is_corresponding":false},{"id":256176,"name":"Mehdi Damaghi","orcid":"0000-0002-7744-6161","position":5,"is_corresponding":false},{"id":65782,"name":"Robert J. Gillies","orcid":"0000-0002-8888-7747","position":6,"is_corresponding":false},{"id":3484,"name":"Christopher J. Whelan","orcid":"0000-0001-7511-2603","position":7,"is_corresponding":false},{"id":330497,"name":"Mariyah Pressley","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:15:34.966380Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}