Accumulation of hypoxia-inducible factor-1alpha is limited by transcription-dependent depletion.
In the presence of oxygen and iron, hypoxia-inducible factor (HIF-1alpha) is rapidly degraded via the prolyl hydroxylases (PHD)/VHL pathways. Given striking similarities between p53 and HIF-1alpha regulation, we previously suggested that HIF-1 transcriptionally initiates its own degradation and therefore inhibitors of transcription must induce HIF-1alpha. Under normoxia, while inducing p53, inhibitors of transcription did not induce HIF-1alpha. Under hypoxia or low iron (DFX), inhibitors of transcription dramatically super-induced HIF-1alpha. Removal of inhibitors resulted in outburst of the HIF-1-dependent transcription followed by depletion of HIF-1alpha. Although hypoxia/DFX induced PHD3, we excluded the PHD/VHL pathway in the regulation of HIF-1alpha under hypoxia/DFX. The transcription-dependent degradation of HIF-1alpha under hypoxia occurs via the proteasome and is accelerated by protein acetylation. Thus, HIF-1alpha is regulated by two distinct mechanisms. Under normoxia, HIF-1alpha is degraded via the classic PHD/VHL pathway, is expressed at low levels and therefore does not activate the feedback loop. But under hypoxia, HIF-1alpha accumulates and transcriptionally activates its own degradation that is independent from the PHD/VHL pathway.
Demidenko
Zoya N
ZN
Brander Cancer Research Institute, New York Medical College, Valhalla, NY, USA.
Rapisarda
AnnaMaria
A
Garayoa
Mercedes
M
Giannakakou
Paraskevi
P
Melillo
Giovanni
G
Blagosklonny
Mikhail V
MV
D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology; D049308:Dioxygenases; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007501:Iron / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D047630:Depsipeptides; D005419:Flavonoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010880:Piperidines; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D003609:Dactinomycin; C077990:alvocidib; C087123:romidepsin; D007501:Iron; D049308:Dioxygenases; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human