• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia.

Hypoxia-inducible factor-1alpha (HIF1alpha) is a central regulator of the cellular response to hypoxia. Prolyl-hydroxylation of HIF1alpha by PHD enzymes is prerequisite for HIF1alpha degradation. Here, we demonstrate that the abundance of PHD1 and PHD3 are regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases Siah1a/2, under hypoxia conditions. Siah2 null fibroblasts exhibit prolonged PHD3 half-life, resulting in lower levels of HIF1alpha expression during hypoxia. Significantly, hypoxia-induced HIF1alpha expression was completely inhibited in Siah1a/2 null cells, yet could be rescued upon inhibition of PHD3 by RNAi. Siah2 targeting of PHD3 for degradation increases upon exposure to even mild hypoxic conditions, which coincides with increased Siah2 transcription. Siah2 null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin. Thus, the control of PHD1/3 by Siah1a/2 constitutes another level of complexity in the regulation of HIF1alpha during hypoxia.

Pubmed ID: 15210114


  • Nakayama K
  • Frew IJ
  • Hagensen M
  • Skals M
  • Habelhah H
  • Bhoumik A
  • Kadoya T
  • Erdjument-Bromage H
  • Tempst P
  • Frappell PB
  • Bowtell DD
  • Ronai Z



Publication Data

June 25, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA51995
  • Agency: NCI NIH HHS, Id: CA80058
  • Agency: NCI NIH HHS, Id: P30 CA08748

Mesh Terms

  • Animals
  • Blotting, Western
  • Cell Hypoxia
  • Cells, Cultured
  • Female
  • Fibroblasts
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins
  • Precipitin Tests
  • Procollagen-Proline Dioxygenase
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transcription Factors
  • Transcription, Genetic
  • Ubiquitin-Protein Ligases