AbstractHypoxia is a relevant physiological stress associated with many processes such as adaptation to high altitudes or human diseases (e.g. cancer). An essential component responsible to regulate the molecular response to hypoxia in the cell is the transcription factor called Hypoxia Inducible Factor (HIF). HIF has recently been associated with a role in inflammation and immunity. Importantly, HIF-1alpha has shown to be regulated by the major inflammatory responsive transcription factor, NF-kappaB (nuclear factor kappaB). Here it is demonstrated that hypoxia also activates NF-kappaB in the context of a whole organism, Drosophila melanogaster, and that NF-kappaB is essential for the survival of these animals in hypoxia.
The finding that NF-kappaB activation results in HIF stabilisation and activity, suggests a functional involvement of HIF transcription factor in processes where NF-kappaB is involved, in particular in response to infection and inflammation.
In this work, HIF was shown to have a critical role in regulating the innate immune system by repressing NF-kappaB in a context of Drosophila, and also in human cancer cell lines. Importantly, HIF-1alpha depletion resulted in enhancement of CDK6-RelA association, and consequently increased inflammatory cytokines, such as IL-8. Functionally, this was relevant as it led to more angiogenesis in an in vitro model.
A genome-wide analysis was also performed in order to understand the role of HIF in inflammation. This has revealed 2495 potential novel HIF-dependent target genes in inflammation, in which several of them were known hypoxia-induced HIF, or NF-kappaB target genes.
Finally, it was also shown that HIF-1alpha and HIF-1beta physically interact with some NF-kappaB subunits. Additionally, HIF-1beta and HIF-2alpha were shown to be required for full activation of NF-kappaB following TNF-alpha.
With this work, a new layer of complexity of the HIF-NF-kappaB crosstalk has been identified. These findings uncover a novel effect of HIF over the NF-kappaB pathway, with relevance for potential new therapies in inflammatory diseases and cancer.
|Date of Award||2014|
|Sponsors||Fundação para a Ciência e a Tecnologia|
|Supervisor||Sonia Rocha (Supervisor)|