Oxygen sensing is impaired in ATM defective cells

Maria Patrizia Mongiardi, Venturina Stagni, Manuela Natoli, Danilo Giaccari, Igea D'Agnano, Maria Laura Falchetti, Daniela Barilà, Andrea Levi

Research output: Contribution to journalArticle

Abstract

The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cell adaptation to decreasing oxygen levels. High oxygen tension promotes proteasomal degradation of HIF-1α via a pathway that requires hydroxylation of prolines 402 and 564. Low oxygen tension, hypoxia, inactivates the hydroxylases responsible for these modifications through a mechanism that is not fully understood but appears to require mitochondrial respiration and production of Reactive Oxygen Species, ROS. Cells from individuals affected by ataxia telangiectasia syndrome have an impaired mitochondrial activity and a constitutive oxidative stress. Here we show that, in these cells, HIF-1α is efficiently degraded even in condition of low oxygen tension. Mechanistically this depends from a blunted increase in intracellular concentration of ROS in response to hypoxia which in turn is due to an increased cellular capacity of buffering ROS. We suggest that regulation of HIF-1α stability may depend on fold chance of ROS relative to the basal level more than on their absolute value. Since elevated oxidative stress is a hallmark of many human disorders our finding may be relevant to different pathologies.

Original languageEnglish
Pages (from-to)4311-4320
Number of pages10
JournalCell Cycle
Volume10
Issue number24
DOIs
Publication statusPublished - Dec 15 2011

Keywords

  • Ataxia telangiectasia
  • ATM
  • HIF-1
  • Hypoxia
  • Oxidative stress

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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    Mongiardi, M. P., Stagni, V., Natoli, M., Giaccari, D., D'Agnano, I., Falchetti, M. L., Barilà, D., & Levi, A. (2011). Oxygen sensing is impaired in ATM defective cells. Cell Cycle, 10(24), 4311-4320. https://doi.org/10.4161/cc.10.24.18663