γ-Secretase is composed of four proteins that are obligatory for protease activity: presenilin, nicastrin, Aph1, and Pen-2. Despite the progress toward understanding the function of these individual subunits, there is no information available pertaining to the modulation of γ-secretase in response to environmental changes in cells. Here, we show that hypoxia upregulates γ-secretase activity through a direct interaction with Hif-1α, revealing an unconventional function for Hif-1α as an enzyme subunit, which is distinct from its canonical role as a transcription factor. Moreover, hypoxia-induced cell invasion and metastasis are alleviated by either γ-secretase inhibitors or a dominant-negative Notch coactivator, indicating that γ-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals a mechanism in which γ-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1α, under select physiological and pathological conditions. © 2014 The Authors.
CITATION STYLE
Villa, J. C., Chiu, D., Brandes, A. H., Escorcia, F. E., Villa, C. H., Maguire, W. F., … Li, Y. M. (2014). Nontranscriptional role of hif-1α in activation of γ-secretase and notch signaling in breast cancer. Cell Reports, 8(4), 1077–1092. https://doi.org/10.1016/j.celrep.2014.07.028
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