Amyloid precursor protein (APP) affects global protein synthesis in dividing human cells Journal Article

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Authors: Sobol, A.; Galluzzo, P.; Liang, S.; Rambo, B.; Skucha, S.; Weber, M. J.; Alani, S.; Bocchetta, M
Article Title: Amyloid precursor protein (APP) affects global protein synthesis in dividing human cells
Abstract: Hypoxic non-small cell lung cancer (NSCLC) is dependent on Notch-1 signaling for survival. Targeting Notch-1 by means of gamma-secretase inhibitors (GSI) proved effective in killing hypoxic NSCLC. Post-mortem analysis of GSI-treated, NSCLC-burdened mice suggested enhanced phosphorylation of 4E-BP1 at threonines 37/46 in hypoxic tumor tissues. In vitro dissection of this phenomenon revealed that Amyloid Precursor Protein (APP) inhibition was responsible for a non-canonical 4E-BP1 phosphorylation pattern rearrangement-a process, in part, mediated by APP regulation of the pseudophosphatase Styx. Upon APP depletion we observed modifications of eIF-4F composition indicating increased recruitment of eIF-4A to the mRNA cap. This phenomenon was supported by the observation that cells with depleted APP were partially resistant to silvestrol, an antibiotic that interferes with eIF-4A assembly into eIF-4F complexes. APP downregulation in dividing human cells increased the rate of global protein synthesis, both cap- and IRES-dependent. Such an increase seemed independent of mTOR inhibition. After administration of Torin-1, APP downregulation and Mechanistic Target of Rapamycin Complex 1 (mTORC-1) inhibition affected 4E-BP1 phosphorylation and global protein synthesis in opposite fashions. Additional investigations indicated that APP operates independently of mTORC-1. Key phenomena described in this study were reversed by overexpression of the APP C-terminal domain. The presented data suggest that APP may be a novel regulator of protein synthesis in dividing human cells, both cancerous and primary. Furthermore, APP appears to affect translation initiation using mechanisms seemingly dissimilar to mTORC-1 regulation of cap-dependent protein synthesis.
Journal Title: Journal of cellular physiology
Volume: 230
Issue: 5
ISSN: 1097-4652; 0021-9541
Publisher: Wiley Periodicals, Inc  
Journal Place: United States
Date Published: 2015
Start Page: 1064
End Page: 1074
Language: eng
DOI/URL:

10.1002/jcp.24835
Notes: LR: 20150531; CI: (c) 2014; GR: CA134503/CA/NCI NIH HHS/United States; GR: R01 CA134503/CA/NCI NIH HHS/United States; JID: 0050222; 0 (Adaptor Proteins, Signal Transducing); 0 (Amyloid beta-Protein Precursor); 0 (EIF4EBP1 protein, human); 0 (Intracellular Signaling Peptides and Proteins); 0 (Multiprotein Complexes); 0 (Nuclear Proteins); 0 (Phosphoproteins); 0 (RNA Caps); 0 (RNA, Messenger); 0 (STYX protein, human); 0 (mechanistic target of rapamycin complex 1); 1114-81-4 (Phosphothreonine); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.7.- (Eukaryotic Initiation Factor-4A); EC 3.4.- (Amyloid Precursor Protein Secretases); NIHMS691859; OID: NLM: NIHMS691859 [Available on 05/01/16]; OID: NLM: PMC4445069 [Available on 05/01/16]; PMCR: 2016/05/01 00:00; 2014/05/29 [received]; 2014/09/22 [accepted]; ppublish