Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer.
Cell Rep
; 8(4): 1077-92, 2014 Aug 21.
Article
em En
| MEDLINE
| ID: mdl-25131208
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Subunidade alfa do Fator 1 Induzível por Hipóxia
/
Receptores Notch
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Secretases da Proteína Precursora do Amiloide
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Neoplasias Pulmonares
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos