Visit our Expo - Redox and Inflammation signaling 2012

Hypoxia Signaling. Impact on Tumor metabolism, Cell survival and Cell death.
N. M. Mazure. F. Dayan, D. Roux, E. Berra, C. Brahimi-Horn, and J. Pouysségur
Institute of Signaling, Developmental Biology and Cancer Research, CNRS-UMR 6543,
Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France
The function of the Hypoxia-Inducible Factor-1 (HIF-1), the key transcription factor involved
in cellular adaptation to hypoxia is restricted to low oxygen tension (pO 2). As such, this
transcription factor is central in modulating the tumor microenvironment, sensing nutrient
availability and controlling anaerobic glycolysis, intracellular pH, and cell survival.
Degradation and inhibition of the limiting HIF-1" subunit are intimately connected in
normoxia. Hydroxylation of two proline residues by Prolyl Hydroxylase Domain protein 2
(PHD2) earmarks the protein for degradation while hydroxylation of an asparagine residue by
Factor Inhibiting HIF-1 (FIH-1) reduces its transcriptional activity. Indeed, silencing in
normoxia, of either PHD2 or FIH-1, partially induced hypoxic genes, whereas combined
PHD2/FIH-1 silencing generated a full hypoxic gene response. Given the fact that HIF-1"
possesses two transactivation domains (N- and C-TAD), we hypothesized on a possible bifunctional
activity of HIF-1a that could be discriminated by FIH-1, a modifier of the C-TAD.
In human cell lines, engineered to overexpress or silence FIH-1, in response to tetracyclin, we
demonstrate by quantitative RT-PCR that a set of hypoxic genes (CAIX, PHD3, PGKI and
BNIP3) respond differently towards FIH-1 expression. This finding, extended to 30 hypoxiainduced
genes, indicates differential gene expression by the N- and C-TAD in response to the
hypoxic gradient.
We propose that the oxygen-sensitive attenuator FIH-1, together with 2 distinct TADs are
central in setting the gene expression repertoire dictated by the cell pO 2.
In the tumor microenvironment context, we are intrigued by the duality of HIF-1 that can
induce either cell survival or cell death. We will discuss our unpublished work on the
physiological roles played by the HIF-induced pro-apoptotic gene product BNIP3, autophagy
and necrotic cell death.
Ways to exploit this basic knowledge to magnify tumor regression will be presented ?
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