Journal
CELL REPORTS
Volume 8, Issue 4, Pages 1077-1092Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.07.028
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Funding
- NIH RO1 grant [AG026660, CA055349, NIH T32 GM073546]
- Geoffrey Beene Cancer Research Center of MSKCC
- Commonwealth Foundation for Cancer Research
- Experimental Therapeutics Center of MSKCC
- William Randolph Hearst Fund in Experimental Therapeutics
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gamma-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 gamma-secretase in response to environmental changes in cells. Here, we show that hypoxia upregulates gamma-secretase activity through a direct interaction with Hif-1 alpha, revealing an unconventional function for Hif-1 alpha 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 gamma-secretase inhibitors or a dominant-negative Notch coactivator, indicating that gamma-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals a mechanism in which gamma-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1 alpha, under select physiological and pathological conditions.
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