Abstract
Non-canonical NF-κB signalling plays important roles in the development and function of the immune system but it also is deregulated in a number of inflammatory diseases. Although, NF-κB and HIF crosstalk has been documented, this has only been described following canonical NF-κB stimulation, involving RelA/p50 and the HIF-1 dimer. Here, we report that the non-canonical inducer TNFSF14/LIGHT leads to HIF induction and activation in cancer cells. We demonstrate that only HIF-2α is induced at the transcriptional level following non-canonical NF-κB activation, via a mechanism that is dependent on the p52 subunit. Furthermore, we demonstrate that p52 can bind to the HIF-2α promoter in cells. These results indicate that non-canonical NF-κB can lead to HIF signalling implicating HIF-2α as one of the downstream effectors of this pathway in cells.
Highlights
NF-κB is the name of a family of transcription factors that is mostly known for their function in regulation of the cellular response to infection and inflammation [1], but it has pleotropic functions in responses to a number of cellular stresses, such as DNA damage and hypoxia [2]
In view of the strong effect on HIF-2α mRNA we had observed with p52 depletion, we investigated whether there was a direct link between these two genes
NF-κB subunits, p52 and RelB, when LIGHT is used as a stimulus
Summary
NF-κB is the name of a family of transcription factors that is mostly known for their function in regulation of the cellular response to infection and inflammation [1], but it has pleotropic functions in responses to a number of cellular stresses, such as DNA damage and hypoxia [2]. The canonical pathway, responding to stimuli, such as TNF-α and IL-1β, activates the IKK complex, leading to the phosphorylation and inactivation of IκB proteins, and the consequent release of the NF-κB dimers, mainly containing RelA and p50 [5]. In the non-canonical pathway, stimuli, such as B-cell activating Factor, or Lymphotoxin-β, activate the NF-κB activating Kinase (NIK), which phosphorylates and activates IKKα, leading, in turn, to the phosphorylation and processing of p100 into p52 [8]. This event releases primarily the RelB/p52 dimers, able to translocate into the nucleus, and together with additional stimulus-specific inputs activate or repress specific genes in cells. Usual activate NF-κB independent of IKKs, or act on nuclear NF-κB subunits [2]
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