Presenilin-1 regulates induction of hypoxia inducible factor-1α: altered activation by a mutation associated with familial Alzheimer's disease

Gasperi, Rita De; Sosa, Miguel A. Gama; Dracheva, Stella; Elder, Gregory A.

doi:10.1186/1750-1326-5-38

Cited by 35 publications

(27 citation statements)

References 90 publications

(106 reference statements)

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“…In addition, Hif-1α has been shown to interact with other proteins, such as pyruvate kinase M2 (Luo et al, 2011) and presenilin (De Gasperi et al, 2010) to enhance its stability and promote Hif-1α signaling. Presenilin can also regulate the Hif-1α pathways to enhance the expression of Hif-1α through the cleavages of amyloid precursor protein (APP) to generate APP intracellular domain (Kaufmann et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Nontranscriptional Role of Hif-1α in Activation of γ-Secretase and Notch Signaling in Breast Cancer

et al. 2014

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SUMMARY γ-Secretase is composed of four proteins that are obligatory for protease activity: Presenilin, Nicastrin, Aph1 and Pen-2. Despite the progress towards 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 an unprecedented 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.

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Section: Discussionmentioning

confidence: 99%

Nontranscriptional Role of Hif-1α in Activation of γ-Secretase and Notch Signaling in Breast Cancer

et al. 2014

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“…Genotyping was performed as previously described [20]. Heterozygous mice were mated to produce PS1−/− embryos with the day a vaginal plug was detected designated as E0.5.…”

Section: Methodsmentioning

confidence: 99%

“…Protein concentration was determined with the BCA reagent as described by the manufacturer (Pierce). Western blotting was performed as previously described [20]. The following antibodies were used: a rabbit polyclonal anti-fibronectin (1:4000; Sigma Aldrich), a rabbit monoclonal anti-vimentin (1:1500, Cell Signaling, Danvers, MA, USA), a mouse monoclonal antibody against the human PS1 N-terminal fragment (NT.1; 1:500; gift of Dr. Paul Mathews, Nathan Kline Institute, Orangeburg NY, USA) and a mouse monoclonal antibody against the PS1 C-terminal fragment (33B10, 1:1000; gift of Dr. Nikolaos Robakis, Icahn School of Medicine at Mount Sinai, New York, NY, USA).…”

Section: Methodsmentioning

confidence: 99%

Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells

2012

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BackgroundPresenilin-1 (PS1) is a transmembrane protein first discovered because of its association with familial Alzheimer’s disease. Mice with null mutations in PS1 die shortly after birth exhibiting multiple CNS and non-CNS abnormalities. One of the most prominent features in the brains of PS1−/− embryos is a vascular dysgenesis that leads to multiple intracerebral hemorrhages. The molecular and cellular basis for the vascular dysgenesis in PS1−/− mice remains incompletely understood. Because the extracellular matrix plays key roles in vascular development we hypothesized that an abnormal extracellular matrix might be present in endothelial cells lacking PS1 and examined whether the lack of PS1 affects expression of fibronectin a component of the extracellular matrix known to be essential for vascular development.ResultsWe report that primary as well as continuously passaged PS1−/− endothelial cells contain more fibronectin than wild type cells and that the excess fibronectin in PS1−/− endothelial cells is incorporated into a fibrillar network. Supporting the in vivo relevance of this observation fibronectin expression was increased in microvascular preparations isolated from E14.5 to E18.5 PS1−/− embryonic brain. Reintroduction of PS1 into PS1−/− endothelial cells led to a progressive decrease in fibronectin levels showing that the increased fibronectin in PS1−/− endothelial cells was due to loss of PS1. Increases in fibronectin protein in PS1−/− endothelial cells could not be explained by increased levels of fibronectin RNA nor based on metabolic labeling studies by increased protein synthesis. Rather we show based on the rate of turnover of exogenously added biotinylated fibronectin that increased fibronectin in PS1−/− endothelial cells results from a slower degradation of the fibronectin fibrillar matrix on the cell surface.ConclusionsThese studies show that PS1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells. These studies provide molecular clues that may help to explain the origin of the vascular dysgenesis that develops in PS1−/− embryonic mice.

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“…Furthermore, presenilin 1 and HIF-1α physical interaction may protect HIF-1α from degradation through proteasome. Additionally, M146V Psen1 mutation impaired metabolic induction of HIF-1α [65]. These data suggest that PS1 regulates the induction of HIF-1α.…”

Section: Hif-1α Interactionmentioning

confidence: 66%

Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

Wężyk¹,

Żekanowski²

2017

Senescence - Physiology or Pathology

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Alzheimer's disease (AD) is the most common type of dementia characterized by massive neuronal loss. Pathological hallmarks of the disease are overproduction of β-amyloid (Aβ) and hyperphosphorylation of tau protein accumulated into senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively. SPs with cortical tau pathology are also hallmark of pathological ageing (PA). Recently, an extensive overlap has been shown between Aβ levels and profiles in PA and AD brains, suggesting that PA could be a prodromal AD phase. Presenilins are major components of the γ-secretase complex involved in Aβ production. Furthermore, presenilins interact with players of numerous signalling pathways important in the PA and AD. Integration of various modern research approaches would reinforce the role of presenilins signalling network in brain pathology. These approaches include high-throughput (epi)genetic and transcriptomic analyses, large-scale microscopic imaging studies, immunoaffinity purification or mass spectrometry. Comprehensive integration of these methods is necessary to update the definition of the role of presenilins in AD and PA. Hereby, we summarize the available data on presenilins' functions and interactions. We believe that the systematization of the existing knowledge will stimulate further research and will help reveal the molecular nooks and crannies in Alzheimer's disease and in pathological ageing.

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Presenilin-1 regulates induction of hypoxia inducible factor-1α: altered activation by a mutation associated with familial Alzheimer's disease

Cited by 35 publications

References 90 publications

Nontranscriptional Role of Hif-1α in Activation of γ-Secretase and Notch Signaling in Breast Cancer

Nontranscriptional Role of Hif-1α in Activation of γ-Secretase and Notch Signaling in Breast Cancer

Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells

Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

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