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Interaction between PARP-1 and HIF-2α in the hypoxic response

Oncogene volume 33, pages 891–898 (2014)Cite this article

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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.

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Acknowledgements

We thank Dr Françoise Dantzer, CNRS, Strasbourg (France), for providing the pEGFP-PARP-1 construct. This work was supported by Ministerio de Ciencia e Innovación (SAF2006-01094 and SAF2009-13281-C02-01), Fundación La Caixa (BM06-219-0) and Junta de Andalucía (P07-CTS-0239) to FJO; Ministerio de Educación y Ciencia (SAF2007-64597 and SAF-2010-20067) and the BIZKAIA XEDE Program from the Bizkaia County to EB.

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Author notes

  1. A Gonzalez-Flores, R Aguilar-Quesada, E Berra and F J Oliver: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain

    A Gonzalez-Flores, R Aguilar-Quesada, M I Rodríguez-Lara, L López –Jiménez, M López-Rodríguez, A Peralta-Leal & F J Oliver

  2. Department of Experimental Biology, University of Jaén, Jaén, Spain

    E Siles

  3. CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain

    S Pozo & E Berra

  4. Institute of Biomedical Research Alberto Sols, CSIC, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain

    D Villar & L del Peso

  5. Department of Cellular Biology, Faculty of Sciences, University of Granada, Granada, Spain

    D Martín-Oliva

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  1. A Gonzalez-Flores
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Correspondence to E Berra or F J Oliver.

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Gonzalez-Flores, A., Aguilar-Quesada, R., Siles, E. et al. Interaction between PARP-1 and HIF-2α in the hypoxic response. Oncogene 33, 891–898 (2014). https://doi.org/10.1038/onc.2013.9

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