Transcriptional regulation of APH‐1A and increased γ‐secretase cleavage of APP and Notch by HIF‐1 and hypoxia

@article{Wang2006TranscriptionalRO,
  title={Transcriptional regulation of APH‐1A and increased $\gamma$‐secretase cleavage of APP and Notch by HIF‐1 and hypoxia},
  author={Ruishan Wang and Yun-wu Zhang and Xian Zhang and Runzhong Liu and Xue Zhang and Shui-gen Hong and Kun Xia and Jia-hui Xia and Zhuohua Zhang and Huaxi Xu},
  journal={The FASEB Journal},
  year={2006},
  volume={20},
  pages={E614 - E622}
}
The proteolytic cleavage of Alzheimer β‐amyloid precursor protein (APP) and signaling receptor Notch is mediated by the PS/γ‐secretase complex, which consists of presenilins, nicastrin, APH‐1, and PEN‐2. Although the four components are known to coordinately regulate each other at the protein level, information regarding their transcription regulation is scarce. Here we characterized the 5′‐flanking region of the human APH‐1A gene and identified a 271‐bp fragment containing the transcription… Expand
Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer.
TLDR
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 is revealed. Expand
HIG1, a novel regulator of mitochondrial γ‐secretase, maintains normal mitochondrial function
  • H. Hayashi, H. Nakagami, +11 authors Y. Kaneda
  • Biology, Medicine
  • FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2012
TLDR
HIG1 is a novel modulator of the mitochondrial γ‐secretase complex, and may play a role in the maintenance of normal mitochondrial function, and depletion of HIG1 increased γ-secretase activation and enhanced hypoxia‐induced mitochondrial dysfunction. Expand
p53-dependent control of transactivation of the Pen2 promoter by presenilins
TLDR
Overall, this study describes a p53-dependent regulation of PEN-2 expression by other members of the γ-secretase complex, namely presenilins. Expand
The up‐regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1α
TLDR
This study significantly extends findings both in vitro, in differentiated SK‐N‐BE neuroblastoma cells, and in vivo, in rats subjected to cerebral ischemia, showing that hypoxia up‐regulates BACE1 expression through a biphasic mechanism, and strengthens the hypothesis that oxidative stress is a basic common mechanism of amyloid‐β accumulation. Expand
Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation*
TLDR
An important role for hypoxia/HIF-1α in modulating the amyloidogenic processing of APP is demonstrated and a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries is provided. Expand
Intracellular Trafficking of Presenilin 1 Is Regulated by β-Amyloid Precursor Protein and Phospholipase D1*
TLDR
It is demonstrated that APP can reciprocally regulate PS1 trafficking and suggested that intracellular trafficking of PS1/γ-secretase is regulated by multiple factors, including APP and PLD1. Expand
Rosuvastatin and Thapsigargin Modulate γ-Secretase Gene Expression and APP Processing in a Human Neuroglioma Model
TLDR
Evidence is provided that rosuvastatin alters gene expression of the γ-secretase complex without affecting enzyme activity, and this statin down-regulated the transcription of some enzyme cofactors, similar to treatment with thapsigargin. Expand
Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP
TLDR
An important role of hypoxia is suggested in modulating the APP processing by facilitating both - and-cleavage which may result in a significant increase of A generation. Expand
Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease
TLDR
Recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating β‐ and γ‐secretases is reviewed, with postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. Expand
Hypoxia Affects Neprilysin Expression Through Caspase Activation and an APP Intracellular Domain-dependent Mechanism
TLDR
Activation of caspases might play an important role in regulation of NEP levels in the brain under pathological conditions such as hypoxia and ischaemia leading to a deficit of Aβ clearance and increasing the risk of development of AD. Expand
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It is demonstrated that endogenous PEN-2 preferentially interacts with PS1 holoprotein, revealing a direct role of P EN-2 in proteolytic cleavage of PS1 and a regulatory function of APH-1, in coordination with Pen-2, in the biogenesis of the PS1 complex. Expand
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