Hypoxia-dependent regulation of PHD1: cloning and characterization of the human PHD1/EGLN2 gene promoter

Abstract

The recent identification of hypoxia-inducible-factor (HIF) prolyl hydroxylases (PHD1, 2, and 3), which modify HIF-1 alpha in an oxygen-dependent manner, provided an important link between oxygen availability and hypoxia-induced gene expression. However, little is known about the regulation of the PHDs. To investigate the transcriptional regulation of PHD1, we cloned the PHD1 gene promoter. Here, we report that the expression of PHD1 is reduced under hypoxic conditions. Furthermore, we identified binding sites for aryl hydrocarbon nuclear translocator (ARNT/HIF-1 beta) within the PHD1 promoter, and showed that ARNT is associated in vivo with the PHD1 promoter following hypoxia, which implies a role for ARNT in the hypoxia-dependent regulation of PHD1. Taken together, our findings suggest a hypoxia-induced regulatory loop of PHD1 expression, mediated by ARNT.