Negative regulation of hypoxia inducible factor-1alpha by necdin.
Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that mediates cellular and systemic homeostatic responses to reduce O2 availability, such as erythropoiesis, angiogenesis, and glycolysis. Using the yeast two-hybrid screening system, we found that the oxygen dependent degradation (ODD) domain of HIF-1alpha interacts with necdin, a growth suppressor. The interaction of necdin with HIF-1alpha was confirmed using coimmunoprecipitation with the overexpressed HIF-1alpha. Biological effect of necdin on HIF-1alpha showed that necdin reduces the transcriptional activity of HIF-1 under hypoxia. Moreover, necdin decreased the level of the HIF-1alpha protein, but not that of mRNA, implying a possibility of necdin-mediated HIF-1alpha degradation. Furthermore, necdin has an anti-angiogenic activity in the tube formation assay and CAM assay, which might be due to the downregulation of HIF-1alpha. Collectively, these results suggest that necdin can be a novel negative regulator of HIF-1alpha stability via the direct interaction.
Moon
Hyo-Eun
HE
Neurovascular Coordination Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Ahn
Mee-Young
MY
Park
Jeong Ae
JA
Min
Kyung-Jin
KJ
Kwon
Yoo-Wook
YW
Kim
Kyu-Won
KW
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C069766:necdin; D010100:Oxygen