Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease

Belyaev, Nikolai D.; Nalivaeva, Natalia N.; Makova, Natalia Z.; Turner, Anthony J.

doi:10.1038/embor.2008.222

Cited by 156 publications

(171 citation statements)

References 31 publications

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“…According to the manufacturer, the specificity of the Silencer select siRNAs was validated by TaqMan gene expression assays. Specific knockdown of APP by Silencer select siRNA has been shown previously (28). After 48 h, cell lysates and media were collected and analyzed using the protocol for cell lysis described above.…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

110

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The ␤-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APP␣. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP downregulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. ␤-Amyloid precursor protein (APP)2 is a highly conserved single transmembrane protein (type I) with a receptor-like structure and consists of a heterogeneous group of proteins migrating between 110 and 135 kDa (1, 2). The heterogeneity is due to alternative splicing, leading to eight distinct isoforms (namely APP677, APP695, APP696, APP714, APP733, APP751, APP752, and APP770), as well as by a variety of post-translational modifications, including O-and N-glycosylation, sulfation, and phosphorylation. APP isoforms exist as immature (N-glycosylated) and mature (N-and O-glycosylated, tyrosylsulfated) species. Immature APP localizes in the endoplasmic reticulum and cis-Golgi, and the mature APP form preferentially localizes in the trans-Golgi network, secretory and endocytic vesicles, and at the plasma membrane (3, 4).APP695 is the most common isoform in the central nervous system, whereas APP751 and APP770 are predominantly expressed in non-neuronal cells (5). The key event in the pathogenic cascade in Alzheimer disease is the amyloidogenic pathway characterized by subsequent cleavage of APP by the enzyme ␤-secretase and further processing by ␥-secretase, which finally leads to the generation of A␤ peptides. However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6, 7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence ...

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Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

110

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“…p53 was shown to regulate PrP C at the transcriptional level by interacting with its promoter, resulting in changes in PrP C mRNA and protein expression. Previous work by the same authors 35 and others 36 has reported that the AICD acts as a transcription factor and that one of its target genes is the Aβ-degrading enzyme neprilysin.…”

Section: P53-dependent Transcriptional Control Of Prp C By Presenilinsmentioning

confidence: 99%

Prion protein and Alzheimer disease

Kellett

Hooper

2009

Prion

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“…In other studies to identify AICD-regulated genes, however, the binding of AICD to regulatory cis-elements has only been demonstrated for a limited set of genes. The targets that have been reported to be up-regulated included the metastasis suppressor KAI1/CD82 (60,61), the tumor suppressor TP53 (62), the A␤-degrading enzyme neprilysin (NEP) (42,(62)(63)(64), the endoplasmic reticulum stress and unfolded protein response gene CHOP/DDIT3 (C/EBP homologous protein/ DNA damage-inducible transcript 3) (65), and sonic hedgehog receptor Patched (PTCH1) (66). In contrast, down-regulated targets included the epidermal growth factor receptor (EGFR) (67) and the low density lipoprotein receptorrelated protein 1 (LRP1) (68).…”

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 99%

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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Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease

Cited by 156 publications

References 31 publications

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Prion protein and Alzheimer disease

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

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