{"doi":"10.1101/2021.05.04.442650","title":"The Hypoxia Response Pathway Promotes PEP Carboxykinase Expression And Gluconeogenesis","abstract":"ABSTRACT Actively dividing cells, including some cancers, rely on aerobic glycolysis rather than oxidative phosphorylation to generate energy, a phenomenon termed “the Warburg effect 1 .” Constitutive activation of the Hypoxia Inducible Factor (HIF-1), a transcription factor known for mediating an adaptive response to oxygen deprivation (hypoxia), is a hallmark of the Warburg effect 2 . HIF-1 is thought to promote glycolysis and suppress oxidative phosphorylation. Here, we show instead that HIF-1 can promote gluconeogenesis. Using a multiomics approach, we determined the genomic, transcriptomic, and metabolomic landscapes regulated by constitutively active HIF-1 in C. elegans . We performed RNA-seq and ChIP-seq under aerobic conditions in mutants lacking EGL-9, a key negative regulator of HIF-1, and then integrated these approaches to identify over a hundred genes directly and functionally upregulated by HIF-1. We show that HIF-1 directly promotes the expression of PCK-1, a PEP carboxykinase that is a rate-limiting mediator of gluconeogenesis 3 . This activation of PCK-1 by HIF-1 promotes survival in response to both oxidative and hypoxic stress. Our work is the first to identify functional direct targets of HIF-1 in vivo , and it describes the first complete metabolome induced by constitutive HIF-1 activation in any organism.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218686,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":573774,"name":"Stephanie M. Pyonteck","orcid":"0000-0002-4143-0969","position":1,"is_corresponding":false},{"id":574281,"name":"Tarmie L. Matlack","orcid":null,"position":2,"is_corresponding":false},{"id":816788,"name":"Aparna Prashar","orcid":null,"position":3,"is_corresponding":false},{"id":816789,"name":"Nanci S. Kane","orcid":null,"position":4,"is_corresponding":false},{"id":17872,"name":"Premal Shah","orcid":"0000-0002-8424-4218","position":5,"is_corresponding":false},{"id":526647,"name":"Christopher Rongo","orcid":"0000-0002-1361-5288","position":6,"is_corresponding":false},{"id":756913,"name":"Mehul Vora","orcid":"0000-0002-1239-6458","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:53:29.626149Z","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":[]}