Increased AICD generation does not result in increased nuclear translocation or activation of target gene transcription

Waldron, Elaine; Isbert, Simone; Kern, Andreas; Jaeger, Sébastian; Martin, Anne Marie; Hébert, Sébastien S.; Behl, Christian; Weggen, Sascha; Strooper, Bart De; Pietrzik, Claus U.

doi:10.1016/j.yexcr.2008.05.003

Cited by 42 publications

(35 citation statements)

References 67 publications

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“…These changes were not related to altered ␣-or ␥-secretase activities, nor were there any obvious indications that a direct ␦OR-APP interaction in a variant-specific manner plays a role in the altered APP processing. Interestingly enough, the APP pro- cessing phenotype in the ␦OR-Cys27 variant-expressing cells is intriguingly similar to that observed previously with APP under pH-neutralized conditions (45), suggesting that these two conditions may share common mechanistic features. ␦OR-Cys27 variant-induced changes in APP processing can be suppressed by a long-term treatment with ␦OR-specific ligands via a mechanism involving altered trafficking of the receptor.…”

Section: Resultssupporting

confidence: 83%

“…Under those conditions in ammonium chloride-treated CHO cells, the accumulation specifically of APP C83, but not APP C99, was detected in conjunction with decreased A␤ and unaltered sAPP␣ levels. APP C99 was also partially converted to APP C83 through an ␣-secretase-mediated cleavage in CHO cells stably overexpressing APP C99 under pH-neutralizing conditions, explaining the decreased APP C99/C83 ratio (45). Consistent with this finding, it was recently shown that C99 and C89 are processed by ␣-secretase (ADAM10) to C83 (16).…”

Section: Vol 31 2011supporting

confidence: 55%

“…on May 10, 2018 by guest http://mcb.asm.org/ ␦OR-Cys27 variant expression was found to result in altered APP processing that is intriguingly similar to the APP processing phenotype under pH-neutralizing conditions (45). Under those conditions in ammonium chloride-treated CHO cells, the accumulation specifically of APP C83, but not APP C99, was detected in conjunction with decreased A␤ and unaltered sAPP␣ levels.…”

Section: Vol 31 2011mentioning

confidence: 76%

“…APP C83 has previously been shown to accumulate under pH-neutralizing conditions. This was suggested to take place because of reduced degradation of C83 in the LEL compartment as well as through partial ␣-secretase-mediated conversion of C99 to C83 (45). Therefore, we wanted to elucidate whether overexpression of the ␦OR-Cys27 variant affected the subcellular localization of APP CTFs in SH-SY5Y-APP751 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

Sarajärvi

Tuusa

Haapasalo

et al. 2011

Molecular and Cellular Biology

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Agonist-induced activation of the ␦-opioid receptor (␦OR) was recently shown to augment ␤-and ␥-secretase activities, which increased the production of ␤-amyloid peptide (A␤), known to accumulate in the brain tissues of Alzheimer's disease (AD) patients. Previously, the ␦OR variant with a phenylalanine at position 27 (␦OR-Phe27) exhibited more efficient receptor maturation and higher stability at the cell surface than did the less common cysteine (␦OR-Cys27) variant. For this study, we expressed these variants in human SH-SY5Y and HEK293 cells expressing exogenous or endogenous amyloid precursor protein (APP) and assessed the effects on APP processing. Expression of ␦OR-Cys27, but not ␦OR-Phe27, resulted in a robust accumulation of the APP C83 C-terminal fragment and the APP intracellular domain, while the total soluble APP and, particularly, the ␤-amyloid 40 levels were decreased. These changes upon ␦OR-Cys27 expression coincided with decreased localization of APP C-terminal fragments in late endosomes and lysosomes. Importantly, a long-term treatment with a subset of ␦OR-specific ligands or a c-Src tyrosine kinase inhibitor suppressed the ␦OR-Cys27-induced APP phenotype. These data suggest that an increased constitutive internalization and/or concurrent signaling of the ␦OR-Cys27 variant affects APP processing through altered endocytic trafficking of APP.Alzheimer's disease (AD) is the most common neurodegenerative disorder in the aging population. It is neuropathologically characterized by well-known hallmarks, such as extracellular amyloid plaques and intraneuronal neurofibrillary tangles, composed of ␤-amyloid peptide (A␤) and hyperphosphorylated tau, respectively. A␤ is generated from the amyloid precursor protein (APP) after sequential cleavages by ␤ (BACE1)-and ␥-secretases. It is a well-established fact that the molecular mechanisms underlying AD pathogenesis involve alterations in APP processing which lead to increased A␤ production or, alternatively, decreased enzymatic degradation and clearance of A␤ (39). To facilitate the design of novel intervention approaches for AD, it is important to identify and functionally characterize genetic alterations which play a role in AD pathogenesis. A plausible candidate in this context is the OPRD1 gene, encoding the ␦-opioid receptor (␦OR), which was recently shown to form a complex with ␤-and ␥-secretases (28, 40). Following agonist-induced activation, ␦OR mediates coendocytic sorting of this complex to late endosomes and lysosomes (LEL) (28,40), in which compartments A␤ production primarily takes place. Conversely, ␤-and ␥-secretase activities as well as A␤ levels were found to be significantly reduced in transgenic APP/PS1⌬E9 mice (overexpressing human APP with the Swedish mutation together with human presenilin-1 harboring the exon 9 deletion) treated with a selective nonpeptide antagonist for ␦OR (40). These results suggest that the amyloidogenic processing of APP is enhanced upon ␦OR activation and that the selective antagonist-mediated modulation of ␦OR ma...

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Section: Resultssupporting

confidence: 83%

Section: Vol 31 2011supporting

confidence: 55%

Section: Vol 31 2011mentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

Sarajärvi

Tuusa

Haapasalo

et al. 2011

Molecular and Cellular Biology

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“…Although not formally defined as direct targets, the glycogen synthase kinase3␤ (GSK3␤) (59,69,70), APP (59) itself, and BACE1 (59) are considered AICD-regulated genes. However, it has to be noted that other studies did not observe a nuclear transcriptional role of AICD at least with respect to the expression of some of the potential target genes (71)(72)(73).…”

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 79%

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

Multhaup

Huber

Buée

et al. 2015

Journal of Biological Chemistry

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Alzheimer disease (AD) 2 is the most common form of dementia and a leading cause of death. Amyloid-␤ (A␤) peptides of varying length (30 -51 amino acid residues) are produced by the sequential, proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases (1, 2). In the healthy brain, these protein fragments are normally degraded and eliminated. In the AD brain, the 42-amino acid peptide (A␤42) is prone to form aggregated amyloid oligomers, which are believed to contribute to plaque formation and cognitive decline (3-6).The ␥-secretase also liberates an intracellular fragment called AICD composed of up to 50 residues depending on N-terminal variations (7-9). The first identification of the APP intracellular fragment (AICD) and its detection in brain tissue (8) immediately suggested that it has transcriptional activity, like the Notch intracellular domain (NICD). Whether amyloid A␤ represents a biologically inert bypass product of APP processing or can harbor its own function is a leading question in the AD field. A␤ is potentially toxic depending on its biophysical state (10). Equimolar amounts of the A␤ peptides and the C-terminal fragment AICD are derived from the ␤-C-terminal fragment C99 (11), which represents the APP fragment generated by the initial APP cleavage by ␤-secretase (Fig. 1).A seminal discovery concerning the transcriptional regulatory function of the APP cytoplasmic tail was the observation of its complex formation with Fe65 and the histone acetyltransferase Tip60 and transcriptional activity in reporter gene assays (12). Transactivation of transcription requires ␥-secretase activity and nuclear translocation of Fe65 but not of AICD under these assay conditions (13). However, other studies detected AICD in transcriptional complexes on promoters of target genes using ChIP (see below).In addition, there is evidence that soluble APP fragments (sAPP) of the ectodomain can modulate gene transcription in stimulating downstream signaling through unknown sAPP receptor(s) (14). Accumulation of intracellular A␤ species in neuronal cells before plaque formation leading to concomitant loss of MAP2 expression suggested that A␤ may affect expression or turnover of other proteins (15-17). However, it was not clarified whether this occurs at the transcriptional or translational level.Using a variety of techniques, the recently detected uptake of A␤ peptides into the nuclei of cultured cells (as well as in vivo) revealed that A␤42 possesses unique modulatory activity (18). Direct evidence for the presence of (i) nuclear A␤42 in wildtype animals, (ii) the increased level of nuclear A␤42 in APPoverexpressing animals, and (iii) the detection of nuclear A␤ in quantities comparable with other transcription factors imply a certain biological relevance.The second major hallmark of AD pathology is the presence of neurofibrillary tangles and is associated with intracellular Tau aggregates called neurofibrillary tangles and with modified Tau (19). Although the neuronal Tau (tubulin-associated unit...

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The impact of amyloid precursor protein signalling and histone deacetylase inhibition on neprilysin expression in human prostate cells

Beckett

Belyaev

et al. 2011

Intl Journal of Cancer

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The zinc metallopeptidase, neprilysin (NEP), is an endothelin-1 degrading enzyme whose expression is extensively downregulated in prostate cancer. The expression of NEP in neuronal cells is regulated by intramembrane proteolysis of the amyloid precursor protein (APP) through its intracellular domain (AICD) facilitating histone acetylation of the NEP promoter and gene transcription. The present study has examined whether similar mechanisms operate in prostate cell lines. The expression of APP and its processing enzymes (b-and c-secretases) was examined in a number of prostate cell lines, and the effect of c-secretase inhibition was explored on NEP expression and activity. The potential interaction of AICD with the NEP promoter was examined by chromatin immunoprecipitation. Our results indicated that all key components involved in APP processing were expressed in prostate cancer cell lines but suppression of AICD production using a c-secretase inhibitor did not decrease NEP expression and activity, and no direct AICD-NEP promoter interaction could be detected. However, histone deacetylase inhibitors (valproate and trichostatin A) caused a 2-to 3-fold increase in NEP expression in PC-3 cells, and combinatorial treatment with the DNA demethylating agent, AzaC, further increased NEP expression levels. Although AICD is detectable in prostate cell lines, it does not appear to regulate NEP by AICD-mediated signalling. Apart from promoter demethylation, the data suggest that histone acetylation may facilitate partial re-activation of NEP expression in advanced prostate cancer cells. Upregulation of this tumour-suppressing protein may provide a novel therapeutic strategy in prostate cancer.Prostate cancer (PC) is the most frequently diagnosed cancer in western males. Advanced PC in the androgen-independent, chemo-refractory state is extremely life-threatening and currently incurable. In the progression of PC to the more malignant, androgen-independent phenotype, loss of a membrane-bound zinc metallopeptidase, neprilysin (NEP), is commonly found.1,2 NEP is an integral membrane glycoprotein and ectoenzyme which serves to inactivate circulating regulatory peptides.3 NEP has a wide tissue expression including intestinal and kidney epithelium, brain, skeletal muscle, lung and prostate. [4][5][6][7][8] NEP is able to inhibit cancer cell proliferation, migration and promote cell apoptosis during chemotherapy either via degradation of mitogenic neuropeptides such as endothelin-1 (ET-1), or by its direct protein-protein interactions with tumour suppressor PTEN, phosphatidylinositol 3-kinase (PI3K) and ezrin/radixin/moesin (ERM) proteins. 9 In prostate cancer cell lines, there is a reciprocal relation between expression levels of the ET-1 synthetic enzyme, endothelin-converting enzyme-1 (ECE-1) and the ET-1 degrading enzyme, NEP.2 Hence, downregulation of ECE-1 10 or upregulation of NEP 11 are proposed as viable therapeutic strategies in advanced prostate cancer.In the prostate, NEP expression is positively regulated by androgens, ...

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Increased AICD generation does not result in increased nuclear translocation or activation of target gene transcription

Cited by 42 publications

References 67 publications

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

The impact of amyloid precursor protein signalling and histone deacetylase inhibition on neprilysin expression in human prostate cells

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