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Accumulation of hypoxia-inducible factor-1alpha is limited by transcription-dependent depletion.
Oncogene. 2005 Jul 14; 24(30):4829-38.O

Abstract

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.

Authors+Show Affiliations

Brander Cancer Research Institute, New York Medical College, Valhalla, NY, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15897903

Citation

Demidenko, Zoya N., et al. "Accumulation of Hypoxia-inducible Factor-1alpha Is Limited By Transcription-dependent Depletion." Oncogene, vol. 24, no. 30, 2005, pp. 4829-38.
Demidenko ZN, Rapisarda A, Garayoa M, et al. Accumulation of hypoxia-inducible factor-1alpha is limited by transcription-dependent depletion. Oncogene. 2005;24(30):4829-38.
Demidenko, Z. N., Rapisarda, A., Garayoa, M., Giannakakou, P., Melillo, G., & Blagosklonny, M. V. (2005). Accumulation of hypoxia-inducible factor-1alpha is limited by transcription-dependent depletion. Oncogene, 24(30), 4829-38.
Demidenko ZN, et al. Accumulation of Hypoxia-inducible Factor-1alpha Is Limited By Transcription-dependent Depletion. Oncogene. 2005 Jul 14;24(30):4829-38. PubMed PMID: 15897903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Accumulation of hypoxia-inducible factor-1alpha is limited by transcription-dependent depletion. AU - Demidenko,Zoya N, AU - Rapisarda,AnnaMaria, AU - Garayoa,Mercedes, AU - Giannakakou,Paraskevi, AU - Melillo,Giovanni, AU - Blagosklonny,Mikhail V, PY - 2005/5/18/pubmed PY - 2005/8/9/medline PY - 2005/5/18/entrez SP - 4829 EP - 38 JF - Oncogene JO - Oncogene VL - 24 IS - 30 N2 - 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. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/15897903/Accumulation_of_hypoxia_inducible_factor_1alpha_is_limited_by_transcription_dependent_depletion_ L2 - https://doi.org/10.1038/sj.onc.1208636 DB - PRIME DP - Unbound Medicine ER -