Transcriptional repression of hypoxia-inducible factor-1 (HIF-1) by the protein arginine methyltransferase PRMT1.

ABSTRACT: Hypoxia-inducible factors (HIF-1 and HIF-2) are essential mediators for the adaptive transcriptional response of cells and tissues to low-oxygen conditions. Under hypoxia or when cells are treated with various nonhypoxic stimuli, the active HIF-? subunits are mainly regulated through increased protein stabilization. For HIF-1?, it is clear that further transcriptional, translational, and posttranslational regulations are important for complete HIF-1 activity. Novel evidence links hypoxia and HIF-1 to arginine methylation, an important protein modification. These studies suggest that arginine methyltransferases may be important for hypoxic responses. Protein arginine methyltransferase 1 (PRMT1), the predominant arginine methyltransferase, can act as a transcriptional activator or repressor by modifying a diverse set of substrates. In this work, we show that PRMT1 is a repressor of both HIF-1 and HIF-2. The cellular depletion of PRMT1 by small interference RNA targeting leads to increased HIF transcriptional activity. This activation is the result of enhanced HIF-? subunit transcription, which allows increased HIF-? subunit availability. We provide evidence that PRMT1-dependent HIF-1? regulation is mediated through the activities of both specificity protein 1 (Sp1) and Sp3, two transcription factors known to control HIF-1? expression. This study therefore identifies PRMT1 as a novel regulator of HIF-1- and HIF-2-mediated responses.

SUBMITTER: Lafleur VN 

PROVIDER: S-EPMC3952860 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other