Abstract EN:

Hypoxia is defined as a lack of oxygen necessary for the aerobic physiology of the cell. The transcription factor Net (Elk3/Sap-2/Erp) belongs to the ternary complex factors subfamily of the Ets protein. Net is a transcriptional repressor that can be switched to an activator after phosphorylation by the MAP kinases. Net regulates several processes, such as migration, angiogenesis, wound healing and tumorigenesis. Apart from phosphorylation, the pathways regulating Net itself remain to be identified. Interestingly, hypoxia is implicated in all the processes regulated by Net and it induces all its target genes. In hypoxia, Net is polyubiquitylated, exported from the nucleus and degraded by the proteasome. The “prolyl-4-hydroxylases containing-domains” (PHDs), known as the oxygen cellular sensors and inducers of the major factor HIF-1degradationregulate Net. Their inhibition induces a downregulation of Net at the protein level and, conversely, their overexpression delays Net hypoxic degradation. The loss of the transcriptional repressor Net participates in the hypoxic induction of target genes PAI-1, c-fos and egr-1. The phosphorylated form of Net is more stable in hypoxia, which could explain its detection in several tumour types that often have hypoxic regions. Net cooperates with HIF in the hypoxic induction of some genes, but they regulate separately some others. A large scale transcriptional analysis is in progress to estimate their roles. Net mutant mice treated with hypoxia inducer cobalt chloride reveal a potential role of Net in the regulation of the haematocrit. This suggests that Net could play a role in physiological responses in vivo induced in hypoxia. Net downregulation by RNAi inhibits the hypoxic stabilisation of HIF-1 at the protein level. This could be due to an overexpression of PHD 2 and 3 at the transcriptional level as shown by a partial analysis of the microarray results. Thus Net could be a regulator of HIF-1 via the PHDs.