title: Interaction between PARP-1 and HIF-2α in the hypoxic response.
abstract: Hypoxia-inducible factors (HIFs) mediate the transcriptional adaptation of hypoxic cells. The extensive transcriptional programm regulated by HIFs involves the induction of genes controlling angiogenesis, cellular metabolism, cell growth, metastasis, apoptosis, extracellular matrix remodeling and others. HIF is a heterodimer of HIF-α and HIF-β subunits. In addition to HIF-1α, HIF-2α has evolved as an isoform that contributes differently to the hypoxic adaptation by performing non-redundant functions. Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein involved in the control of DNA repair and gene transcription by modulating chromatin structure and acting as part of gene-specific enhancer/promoter-binding complexes. Previous results have shown that PARP-1 regulates HIF-1 activity. In this study, we focused on the cross-talk between HIF-2α and PARP-1. By using different approaches to suppress PARP-1, we show that HIF-2α mRNA expression, protein levels and HIF-2-dependent gene expression, such as ANGPTL4 and erythropoietin (EPO), are regulated by PARP-1. This regulation occurs at both the transcriptional and post-trancriptional level. We also show a complex formation between HIF-2α with PARP-1. This complex is sensitive to PARP inhibition and seems to protect against the von Hippel-Lindau-dependent HIF-2α degradation. Finally, we show that parp-1(-/-) mice display a significant reduction in the circulating hypoxia-induced EPO levels, number of red cells and hemoglobin concentration. Altogether, these results reveal a complex functional interaction between PARP-1 and the HIF system and suggest that PARP-1 is involved in the fine tuning of the HIF-mediated hypoxic response in vivo.
authors: Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
authors: A
authors: A
authors: Gonzalez-Flores
authors: Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
authors: R
authors: R
authors: Aguilar-Quesada
authors: Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors: E
authors: E
authors: Siles
authors: CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain.
authors: S
authors: S
authors: Pozo
authors: Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
authors: M I
authors: MI
authors: Rodríguez-Lara
authors: Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
authors: L
authors: L
authors: López-Jiménez
authors: Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
authors: M
authors: M
authors: López-Rodríguez
authors: Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
authors: A
authors: A
authors: Peralta-Leal
authors: Institute of Biomedical Research Alberto Sols, CSIC, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.
authors: D
authors: D
authors: Villar
authors: Department of Cellular Biology, Faculty of Sciences, University of Granada, Granada, Spain.
authors: D
authors: D
authors: Martín-Oliva
authors: Institute of Biomedical Research Alberto Sols, CSIC, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.
authors: L
authors: L
authors: del Peso
authors: CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain.
authors: E
authors: E
authors: Berra
authors: Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
authors: F J
authors: FJ
authors: Oliver
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004921:Erythropoietin / Q000097:blood / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C474772:ANGPTL4 protein, human; C499320:PARP1 protein, human