Authors: | Villa, J. C.; Chiu, D.; Brandes, A. H.; Escorcia, F. E.; Villa, C. H.; Maguire, W. F.; Hu, C. J.; de Stanchina, E.; Simon, M. C.; Sisodia, S. S.; Scheinberg, D. A.; Li, Y. M. |
Article Title: | Nontranscriptional role of hif-1α in activation of γ-secretase and notch signaling in breast cancer |
Abstract: | 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. |
Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; nonhuman; protein function; cell proliferation; animal cell; mouse; animal tissue; cell viability; breast cancer; tumor volume; animal experiment; animal model; protein binding; notch receptor; protein interaction; enzyme activation; in vitro study; enzyme activity; hypoxia; lung metastasis; cell migration; down regulation; tumor growth; protein structure; breast metastasis; hypoxia inducible factor 1alpha; cell invasion; gamma secretase inhibitor; enzyme induction; gamma secretase; procollagen proline 2 oxoglutarate 4 dioxygenase; human; female; priority journal; article; hypoxia inducible factor 1beta; prolyl hydroxylase 2 |
Journal Title: | Cell Reports |
Volume: | 8 |
Issue: | 4 |
ISSN: | 2211-1247 |
Publisher: | Cell Press |
Date Published: | 2014-08-21 |
Start Page: | 1077 |
End Page: | 1092 |
Language: | English |
DOI: | 10.1016/j.celrep.2014.07.028 |
PROVIDER: | scopus |
PUBMED: | 25131208 |
PMCID: | PMC4346175 |
DOI/URL: | |
Notes: | Export Date: 1 December 2014 -- Source: Scopus |