ER stress and hypoxia response pathways interact to potentiate HIF-1 transcriptional activity on targets like VEGF [Gene Regulation]

December 17th, 2013 by Pereira, E. R., Frudd, K., Awad, W., Hendershot, L. M.

Cells respond to suboptimal micro-environments by activating stress-signaling pathways like the Unfolded Protein Response (UPR) and hypoxia-induced transcription factors, HIF-1/2, to restore homeostasis. Both cytoprotective pathways have been well studied in isolation at the biochemical and molecular levels. Mounting evidence reveals that they can be activated simultaneously in tumor cells, and likely other tissues experiencing inadequate micro-environments, and they share some transcriptional targets, like the proangiogenic factor, VEGFA. However, the potential interaction between these pathways is poorly understood. Cell culture experiments revealed that in response to UPR activation, ATF4 bound to the human VEGFA promoter and activated its transcription, whereas HIF-1 did so in response to hypoxia. When both pathways were activated together, VEGFA transcripts were induced to a higher level than when either stress was applied alone. Surprisingly, this was not due to the combined actions of the stress pathway-specific transcription factors. Instead we found that ER stress potentiated HIF-1 activity to transactivate VEGF expression, as well as another well-characterized target, BNIP3. These data reveal an unexpected interaction between two important cyto-protective responses, which are likely to have significant consequences in environmentally compromised tissues and tumor cells.