title: Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer.
abstract: Studies on erythropoietin regulation led to discovery of hypoxia-inducible factor 1 (HIF-1), a transcription factor which is central component of oxygen sensing mechanism in mammalian cells. The number of HIF-1 and hypoxia-regulated target genes has grown exponentially and includes genes that encode proteins with roles in erythropoiesis, angiogenesis, glycolytic pathway, glucose transport, metastasis, and cell survival. Thus, HIF-1 claimed the role of the master that orchestrates cellular responses to oxygen deprivation. In addition, HIF-1 is also activated or influenced through oxygen-independent mechanisms via growth factors, deregulated oncogenes, and/or tumor suppressors. Whereas HIF prolyl hydroxylases (PHDs) regulate HIF-1 (and subsequently identified HIF-2) during hypoxia, the PI3K, AKT and MAPK pathways mediate primarily non-hypoxic HIF regulation. Here we will focus primarily on pathways that lead to HIF activation via PI3K/AKT, and mTOR/p70S6K1. In addition, recent studies have revealed novel factors and mechanisms that regulate oxygen-independent HIF-1α and HIF-2α degradation. HIFs play important roles in many processes in health and disease. Consequently, HIFs and pathways (PI3K/AKT and mTOR/p70S6K1) that lead to normoxic HIF activation are considered potential therapeutic targets in these pathologies.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Room 336, Philadelphia, PA 19107, USA. Faton.Agani@jefferson.edu
authors.forename: Faton
authors.initials: F
authors.lastname: Agani
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D055550:Protein Stability; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; D021122:Protein Subunits; D017382:Reactive Oxygen Species; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D015688:Oncogene Protein pp60(v-src); D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases