Oxygen sensing is impaired in ATM-defective cells

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 proteosomal 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 change 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

Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation

“…Hypoxia and HIF-1␣ may also affect directly the activity of the ataxia telangiectasia mutated (ATM) pathway, which plays a critical role in DNA repair in HSCs during aging 33 or after ionizing radiation. [34][35] Indeed, HIF-1␣ is rapidly degraded even in hypoxic conditions in cells with defective ATM kinase, 36 suggesting that ATM is another critical regulator of HIF-1␣ protein stability. Reciprocally, hypoxia activates ATM protein kinase by DNA damage-independent mechanisms.…”

Tug of War between Survival and Death: Exploring ATM Function in Cancer

“…Using Atm −/− mice, the authors demonstrated that the absence of ATM increased the levels of ROS in vivo and caused signs of oxidative stress in the central nervous system, in particular in cells of the cerebellum, the primary site of neurodegeneration in AT patients [81]. More recently, regulation of oxidative stress by ATM has been proposed to play a role in several cellular functions including haematopoietic and neuronal stem cell self-renewal and survival [82–84], RTK activation [85] and hypoxia [86,87], that are often aberrantly regulated in cancer.…”

“…Evidence for a link between ATM and hypoxia has been provided by several laboratories [86,87,95–98]. Importantly, hypoxia has been shown to trigger ATM activation which in turn phosphorylates HIF-1α, a transcription factor that plays a central role in the cellular response to hypoxia, by activating the downstream regulation of metabolism, mitochondrial function and angiogenesis [86].…”

ATM kinase sustains HER2 tumorigenicity in breast cancer

“…The pcDNA3-HER2 construct was kindly provided by P. Nisticò and the shATM construct by Y. Lerenthal and Y. Shiloh 42 . Control shRNA, siR5, has been described 43 .…”