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.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Villa
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Danica
authors.initials: D
authors.lastname: Chiu
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Alissa H
authors.initials: AH
authors.lastname: Brandes
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Freddy E
authors.initials: FE
authors.lastname: Escorcia
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Villa
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Maguire
authors.affiliation: Molecular Biology Graduate Program, School of Dental Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Cheng-Jun
authors.initials: CJ
authors.lastname: Hu
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.affiliation: The Center for Molecular Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA. Electronic address: liy2@mskcc.org.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases