Nontranscriptional role of hif-1α in activation of γ-secretase and notch signaling in breast cancer Journal Article


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
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MSK Authors
  1. Yueming Li
    104 Li
  2. Carlos H Villa
    13 Villa
  3. Jennifer W Chien
    4 Chien
  4. Danica Chiu
    2 Chiu