Altered localization of amyloid precursor protein under endoplasmic reticulum stress

Kudo, Takashi; Okumura, M; Imaizumi, Kazunori; Araki, Wataru; Morita, Takashi; Tanimukai, Hitoshi; Kamagata, Eiichiro; Tabuchi, Nobuhiko; Kimura, Ryo; Kanayama, Daisuke; Fukumori, Akio; Tagami, Shinji; Okochi, Masayasu; Kubo, Mika; Tanii, Hisashi; Tohyama, Masaya; Tabira, Takeshi; Takeda, Masatoshi

doi:10.1016/j.bbrc.2006.03.173

Cited by 55 publications

(50 citation statements)

References 15 publications

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“…Furthermore, co-precipitation studies showed that GRP78 selectively binds to the immature form of APP. These results could suggest that interaction of GRP78 with APP inhibits the translocation from the endoplasmic reticulum lumen to the cis-Golgi network, where maturation is completed (26,77,78). Moreover, semiquantitative comparison of interactomes of APP, APLP1, and APLP2 confirms selective binding of GRP78 to APP but not to APLP1 or APLP2 (79).…”

Section: ␤-Amyloid Precursor Protein Is a Tumor Growth Factormentioning

confidence: 85%

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

111

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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: ␤-Amyloid Precursor Protein Is a Tumor Growth Factormentioning

confidence: 85%

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

111

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“…Several studies have shown that APP holoprotein is degraded by the proteasome under various conditions: proteasomal degradation of APP is enhanced by interrupted N-glycosylation of APP (36) and overexpression of modifier of cell adhesion (MOCA, Dock3) (35) whereas overexpression of peroxisome proliferator-activated receptor-␥ (PPAR␥) induces accumulation of polyubiquitinated APP (46). On the other hand, induction of ER stress results in retention of APP in the early secretory pathway and decreases generation of A␤ (47). Our results showing that (1) immature APP as well as an N-terminally truncated form of APP are retrotranslocated to the cytosol, and (2) both retrotranslocated forms of APP can be degraded by the proteasome and HtrA2, provide a mechanistic explanation for the previously reported findings and identify APP as a novel substrate for ERAD.…”

Section: Discussionmentioning

confidence: 99%

HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation

Huttunen

Guénette

Peach

et al. 2007

Journal of Biological Chemistry

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“…26,31 We and others demonstrated a potential role for ER stress and UPR activation in HAND pathogenesis, as well as in other neurodegenerative diseases. 22,26,32,33 In postmortem brain tissue from ARV-treated, HIV þ patients and AD patients, expression levels of BiP, phosphorylated eIF2a (p-eIF2a), ATF6b, and other UPR markers were increased, primarily in neurons. 26,30,34 Interestingly, Vassar and colleagues 35,36 showed that in vivo UPR activation via glucose deprivation or tunicamycin in the CNS resulted in increased APP and b-amyloid (Ab) deposition 35e37 and that impaired brain energy metabolism lead to chronic PERK activation, sustained eIF2a phosphorylation, and b-site APP cleaving enzyme 1 (BACE1) up-regulation.…”

mentioning

confidence: 99%

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation

Gannon

Akay

Yee

et al. 2017

The American Journal of Pathology

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Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinaseedependent phosphorylation of the eukaryotic translation initiation factor 2a and enhanced translation of b-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced b-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 upregulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders. (Am J Pathol 2017, 187: 91e109; http://dx

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Altered localization of amyloid precursor protein under endoplasmic reticulum stress

Cited by 55 publications

References 15 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

HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation

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