title: The purpose of the HIF-1/PHD feedback loop: to limit mTOR-induced HIF-1α.
abstract: Prolyl hydroxylases (PHDs) target hypoxia-inducible factor-1α (HIF-1α) for degradation. Hypoxia inactivates PHDs, causing accumulation of HIF-1α. In turn, HIF-1 further transactivates PHDs. It is thought that the purpose of this feedback loop is to limit HIF-1α accumulation caused by hypoxia. Here, we suggest that the feedback is intended to limit the induction of HIF-1α by insulin, growth factors, hormones, cytokines and nutrients. These stimuli induce HIF-1α by increasing its translation, not by inhibiting PHDs. As exemplified herein, in a mTOR-dependent manner, insulin transiently induced HIF-1α in retinal pigment epithelial (RPE) cells. Induction of HIF-1α was followed by activation of HIF-dependent transcription. Furthermore, DFX, which inactivates PHDs, potentiated the induction of HIF-1α by insulin. We propose that the most relevant function of the PHD-HIF feedback loop is to limit the induction of HIF-1α by mTOR. The failure to limit mTOR-dependent induction of HIF-1 may contribute to age-related macular degeneration and diabetic retinopathy, suggesting rapamycin for prevention of these age-related diseases.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute; Buffalo NY, USA.
authors.forename: Zoya N
authors.initials: ZN
authors.lastname: Demidenko
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D015687:Cell Hypoxia; D003676:Deferoxamine / Q000494:pharmacology; D049308:Dioxygenases / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007328:Insulin / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D049308:Dioxygenases; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D003676:Deferoxamine