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  • The EMBO Journal (2008) 27, 2545 - 2556
  • doi:10.1038/emboj.2008.180

Published online: 11 September 2008

CSB protein is (a direct target of HIF-1 and) a critical mediator of the hypoxic response

Silvia Filippi1, Paolo Latini1, Mattia Frontini2, Fabrizio Palitti1, Jean-Marc Egly3 and Luca Proietti-De-Santis1

  1. Laboratory of Molecular Cytogenetics and Mutagenesis, Department ABAC, University of Tuscia, Viterbo, Italy
  2. MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, UK
  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM, Illkirch, CU Strasbourg, France

Correspondence to:

Jean-Marc Egly, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France. Tel.: +33 388 65 34 47; Fax: +33 388 65 32 01; E-mail: egly@igbmc.u-strasbg.fr

Luca Proietti-De-Santis, Laboratory of Molecular Cytogenetics and Mutagenesis, Department ABAC, University of Tuscia, Via S. Camillo de Lellis snc, 1100 Viterbo, Italy. Tel.: +39 076 135 7207; Fax: +39 076 135 7242; E-mail: proietti@unitus.it

Received 7 May 2008; Accepted 14 August 2008

Cockayne syndrome (CS) is a rare genetic disease characterized by neurological problems, growth failure and premature ageing. Many of these features cannot simply be ascribed to the defect that CS cells display during transcription-coupled repair. Here, we show that CSB mutant cells are unable to react to hypoxic stimuli by properly activating the hypoxia-inducible factor-1 (HIF-1) pathway, a defect that is further enhanced in the event of a concomitant genotoxic stress. Furthermore, we show that CSB expression is under the control of HIF-1 and has a critical function during hypoxic response by redistributing p300 between HIF-1 and p53. Altogether, our data demonstrate that CSB is part of a feedback loop mechanism that modulates the biological functions of p53. The outcome of this study provides new insights into the understanding of the molecular basis of the CS phenotype and the involvement of the CSB protein in the hypoxic response pathway.

  • Keywords:

    • CSB,
    • HIF-1,
    • p53,
    • p300