Dataset Information

Nontranscriptional role of Hif-1? in activation of ?-secretase and notch signaling in breast cancer.

ABSTRACT: ?-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 ?-secretase in response to environmental changes in cells. Here, we show that hypoxia upregulates ?-secretase activity through a direct interaction with Hif-1?, revealing an unconventional function for Hif-1? 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 ?-secretase inhibitors or a dominant-negative Notch coactivator, indicating that ?-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals a mechanism in which ?-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1?, under select physiological and pathological conditions.

SUBMITTER: Villa JC

PROVIDER: S-EPMC4346175 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer.

Villa Jennifer C JC Chiu Danica D Brandes Alissa H AH Escorcia Freddy E FE Villa Carlos H CH Maguire William F WF Hu Cheng-Jun CJ de Stanchina Elisa E Simon M Celeste MC Sisodia Sangram S SS Scheinberg David A DA Li Yue-Ming YM

Cell reports 20140814 4

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 sub ...[more]

PMID: 25131208

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Project description:BackgroundEpithelial-mesenchymal transition (EMT) of mesothelial cells is a key step in the peritoneal fibrosis (PF). Recent evidence indicates that signal transducer and activator of transcription 3 (STAT3) might mediate the process of renal fibrosis, which could induce the expression of hypoxia-inducible factor-1α (HIF-1α). Here, we investigated the effect of STAT3 activation on HIF-1α expression and the EMT of mesothelial cells, furthermore the role of pharmacological blockade of STAT3 in the process of PF during peritoneal dialysis (PD) treatment.MethodsFirstly, we investigated the STAT3 signaling in human peritoneal mesothelial cells (HPMCs) from drained PD effluent. Secondly, we explored the effect of STAT3 signaling activation on the EMT and the expression of HIF-1α in human mesothelial cells (Met-5A) induced by high glucose. Finally, peritoneal fibrosis was induced by daily intraperitoneal injection with peritoneal dialysis fluid (PDF) so as to explore the role of pharmacological blockade of STAT3 in this process.ResultsCompared with the new PD patient, the level of phosphorylated STAT3 was up-regulated in peritoneal mesothelial cells from long-term PD patients. High glucose (60 mmol/L) induced over-expression of Collagen I, Fibronectin, α-SMA and reduced the expression of E-cadherin in Met-5A cells, which could be abrogated by STAT3 inhibitor S3I-201 pretreatment as well as by siRNA for STAT3. Furthermore, high glucose-mediated STAT3 activation in mesothelial cells induced the expression of HIF-1α and the profibrotic effect of STAT3 signaling was alleviated by siRNA for HIF-1α. Daily intraperitoneal injection of high-glucose based dialysis fluid (HG-PDF) induced peritoneal fibrosis in the mice, accompanied by the phosphorylation of STAT3. Immunostaining showed that phosphorylated STAT3 was expressed mostly in α-SMA positive cells in the peritoneal membrane induced by HG-PDF. Administration of S3I-201 prevented the progression of peritoneal fibrosis, angiogenesis, macrophage infiltration as well as the expression of HIF-1α in the peritoneal membrane induced by high glucose.ConclusionsTaken together, these findings identified a novel mechanism linking STAT3/HIF-1α signaling to peritoneal fibrosis during long-term PD treatment. It provided the first evidence that pharmacological inhibition of STAT3 signaling attenuated high glucose-mediated mesothelial cells EMT as well as peritoneal fibrosis.

Dataset Information

Nontranscriptional role of Hif-1? in activation of ?-secretase and notch signaling in breast cancer.

Publications

Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer.

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