Transcriptional repression of hypoxia-inducible factor-1 (HIF-1) by the protein arginine methyltransferase PRMT1.
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-α subunits are mainly regulated through increased protein stabilization. For HIF-1α, 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-α subunit transcription, which allows increased HIF-α subunit availability. We provide evidence that PRMT1-dependent HIF-1α regulation is mediated through the activities of both specificity protein 1 (Sp1) and Sp3, two transcription factors known to control HIF-1α expression. This study therefore identifies PRMT1 as a novel regulator of HIF-1- and HIF-2-mediated responses.
Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, and Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 2J6, Canada Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, and Departments of Oncology and Medicine, McGill University, Montréal, QC H3G 1Y6, Canada.
Véronique N
VN
Lafleur
Stéphane
S
Richard
Darren E
DE
Richard
D001120:Arginine / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
D001120:Arginine; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases; D011484:Protein-Arginine N-Methyltransferases; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497121:SP3 protein, human; C099988:PRMT1 protein, human