Precursor cystatin C in cultured retinal pigment epithelium cells: evidence for processing through the secretory pathway

Paraoan, Luminita; White, Mike; Spiller, David G.; Grierson, Ian; Maden, B.E.H.

doi:10.1080/09687680110075101

Cited by 24 publications

(5 citation statements)

References 27 publications

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“…All cell lines transfected with pGFP‐PERP construct showed marked plasma membrane‐associated fluorescence, with additional perinuclear localization in the cytoplasm, previously identified as the endoplasmic reticulum (ER)/Golgi apparatus [36, 37], and with no detectable fluorescence signal in the nucleus (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma

Davies

Gray

Spiller

et al. 2008

J Cellular Molecular Medi

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IntroductionCell death by apoptosis is critical for the health of multi-cellular organisms being involved both in the development and in the maintenance of tissue homeostasis, as well as in the elimination of abnormal cells [1]. The transcription factor p53 is part of a complex signalling network involved in the regulation of cellular responses to oncogenic stress, including DNA damage, which performs its tumour suppression role by either inducing cell cycle arrest (in G1 and/or G2) or eliminating abnormal cells by apoptosis [2][3][4]. The function of p53 as a tumour suppressor is underlined by the presence of its mutations in approximately half of human cancers [5], whereas the p53 pathway is compromised by other means in the majority of other cancers [3,6]. The mechanism by which p53 activates cell cycle arrest is far better characterized [7][8][9] Abstract p53 apoptosis effector related to PMP-22 (PERP) is a transcriptional target gene of p53 tumour suppressor that is specifically induced during apoptosis and not during cell cycle arrest. In primary uveal melanoma (UM), the most common intraocular malignancy in adults that has a reportedly unaffected signalling pathway upstream of and including p53, PERP expression is down-regulated in the metastatic monosomy 3-type tumours, compared with the less aggressive disomy 3-type tumours. Here, we demonstrate experimentally, by the use of full-length PERP-green fluorescent protein (GFP) fusions and real-time confocal microscopy, the intracellular targeting and plasma membrane localization of PERP in living UM cells and show that expression of PERP induces caspase-mediated apoptosis in UM cells. Induction of PERP expression in GFP-PERP-transfected UM cells leads to increased levels of cleaved caspase-8 forms, as well as to reduction of its full

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Section: Resultsmentioning

confidence: 99%

P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma

Davies

Gray

Spiller

et al. 2008

J Cellular Molecular Medi

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“…Two of the mutations in the presenilin 2 gene that are linked to FAD (PS2 M239I and T122R) alter CysC trafficking in mouse primary neurons and cause reduced CysC secretion (Ghidoni et al, 2007). The primary structure of CysC is indicative of a secreted protein and accordingly, it was demonstrated that most of the CysC is targeted extracellularly via the secretory pathway (Wei et al, 1998; Paraoan et al, 2001). Moreover, it was recently shown that CysC is also secreted in association with exosomes (Ghidoni et al, 2011).…”

Section: Cysc and Alzheimer's Diseasementioning

confidence: 99%

Cystatin C in Alzheimer's disease

Kaur¹,

Levy²

2012

Front. Mol. Neurosci.

110

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Changes in expression and secretion levels of cystatin C (CysC) in the brain in various neurological disorders and in animal models of neurodegeneration underscore a role for CysC in these conditions. A polymorphism in the CysC gene (CST3) is linked to increased risk for Alzheimer's disease (AD). AD pathology is characterized by deposition of oligomeric and fibrillar forms of amyloid β (Aβ) in the neuropil and cerebral vessel walls, neurofibrillary tangles composed mainly of hyperphosphorylated tau, and neurodegeneration. The implication of CysC in AD was initially suggested by its co-localization with Aβ in amyloid-laden vascular walls, and in senile plaque cores of amyloid in the brains of patients with AD, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), and cerebral infarction. CysC also co-localizes with Aβ amyloid deposits in the brains of non-demented aged individuals. Multiple lines of research show that CysC plays protective roles in AD. In vitro studies have shown that CysC binds Aβ and inhibits Aβ oligomerization and fibril formation. In vivo results from the brains and plasma of Aβ-depositing transgenic mice confirmed the association of CysC with the soluble, non-pathological form of Aβ and the inhibition of Aβ plaques formation. The association of CysC with Aβ was also found in brain and in cerebrospinal fluid (CSF) from AD patients and non-demented control individuals. Moreover, in vitro results showed that CysC protects neuronal cells from a variety of insults that may cause cell death, including cell death induced by oligomeric and fibrillar Aβ. These data suggest that the reduced levels of CysC manifested in AD contribute to increased neuronal vulnerability and impaired neuronal ability to prevent neurodegeneration. This review elaborates on the neuroprotective roles of CysC in AD and the clinical relevance of this protein as a therapeutic agent.

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“…Newly synthesized CysC is secreted from all cell types 19–24 , secreted CysC can be internalized into cells via endocytosis 25–27 , and uptake of CysC can occur by cells other than the cell producing the protein 25–27 , suggesting that in vivo CysC can mediate important communications between cells. In addition to being targeted to the classical secretory pathway, CysC is secreted in association with EVs 28 .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection mediated by cystatin C-loaded extracellular vesicles

Pérez‐González

Sahoo

Gauthier

et al. 2019

Sci Rep

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Cystatin C (CysC) is implicated in neuroprotection and repair in the nervous system in response to diverse neurotoxic conditions. In addition to being secreted from cells in a soluble form, CysC is released by cells in association with extracellular vesicles (EVs), including exosomes. We demonstrate that EVs containing CysC protect cultured cells from starvation-induced death. Moreover, while EVs secreted by CysC-deficient cells were not protective, EVs secreted by CysC-deficient cells treated with exogenous human CysC significantly enhanced the survival of the cells. CysC also plays a role in modulating the secretion of EVs, enhancing secretion of EVs by primary cortical neurons and primary cortical smooth muscle cells. Confirming these in vitro findings, higher EV levels were observed in the brain extracellular space of transgenic mice expressing human CysC as compared to littermate controls. Regulation of cell-secreted EV levels and content in the brain is likely to be essential to maintaining normal brain function. We propose that enhanced EV release could rescue the deleterious effects of dysfunction of the endosomal-lysosomal system in neurodegenerative disorders. Moreover, a higher level of CysC-loaded EVs released from cells in the central nervous system has important protective functions, representing a potential therapeutic tool for disorders of the central nervous system.

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Precursor cystatin C in cultured retinal pigment epithelium cells: evidence for processing through the secretory pathway

Cited by 24 publications

References 27 publications

P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma

P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma

Cystatin C in Alzheimer's disease

Neuroprotection mediated by cystatin C-loaded extracellular vesicles

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