Transcriptional and Post-Transcriptional Regulation of Proangiogenic Factors by the Unfolded Protein Response

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Abstract
Inadequate extracellular conditions can adversely affect the environment of the ER and impinge on the maturation of nascent proteins. The resultant accumulation of unfolded proteins activates a signal transduction pathway, known as the unfolded protein response, which serves primarily to protect the cell during stress and helps restore homeostasis to the ER. Microarray analysis of the unfolded protein response in a human medulloblastoma cell line treated with thapsigargin revealed that, in addition to known targets, a large number of proangiogenic factors were up-regulated. Real-Time PCR analyses confirmed that four of these factors, VEGFA, FGF2, angiogenin and IL8, were transcriptionally up-regulated in multiple cell lines by various ER stress inducers. Our studies on VEGFA regulation revealed that XBP-1(S), a UPR-inducible transcription factor, bound to two regions on the VEGFA promoter, and analysis of XBP-1 null mouse embryonic fibroblasts revealed that it contributes to VEGFA expression in response to ER stress. ATF4, another UPR-inducible transcription factor, also binds to the VEGFA gene, although its contribution to VEGFA transcription appeared to be fairly modest. We also found that VEGFA mRNA stability is increased in response to UPR activation, via activation of AMP kinase, demonstrating that increased mRNA levels occur at two regulatory points. In keeping with the mRNA levels, we found that VEGFA protein is secreted at levels as high as or higher than that achieved in response to hypoxia. Our results indicate that the UPR plays a significant role in inducing positive regulators of angiogenesis. It also regulates VEGFA expression at transcriptional, post-transcriptional and post-translational levels and is likely to have widespread implications for promoting angiogenesis in response to normal physiological cues as well as in pathological conditions like cancer.

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