Article

Zhang YW, Wangt RS, Liu Q, Zhang H, Liao FF, Xu HXPresenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci USA 104:10613-10618

Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2007; 104(25):10613-8. DOI: 10.1073/pnas.0703903104
Source: PubMed

ABSTRACT

Presenilins (PS, PS1/PS2) are necessary for the proteolytic activity of gamma-secretase, which cleaves multiple type I transmembrane proteins including Alzheimer's beta-amyloid precursor protein (APP), Notch, ErbB4, etc. Cleavage by PS/gamma-secretase releases the intracellular domain (ICD) of its substrates. Notch ICD translocates into the nucleus to regulate expression of genes important for development. However, the patho/physiological role of other ICDs, especially APP ICD (AICD), in regulating gene expression remains controversial because evidence supporting this functionality stems mainly from studies performed under supraphysiological conditions. EGF receptor (EGFR) is up-regulated in a wide variety of tumors and hence is a target for cancer therapeutics. Abnormal expression/activation of EGFR contributes to keratinocytic carcinomas, and mice with reduced PS dosages have been shown to develop skin tumors. Here we demonstrate that the levels of PS and EGFR in the skin tumors of PS1(+/-)/ PS2(-/-) mice and the brains of PS1/2 conditional double knockout mice are inversely correlated. Deficiency in PS/gamma-secretase activity or APP expression results in a significant increase of EGFR in fibroblasts. Importantly, we show that AICD mediates transcriptional regulation of EGFR. Furthermore, we provide in vivo evidence demonstrating direct binding of endogenous AICD to the EGFR promoter. Our results indicate an important role of PS/gamma-secretase-generated APP metabolite AICD in gene transcription and in EGFR-mediated tumorigenesis.

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    • "Interestingly, it has come up as one of the most significant candidate in our study occurring in top 10 ranked genes among 108 candidates, as central hub node in cluster and in the overlap of AD protein and proteins from plasma and CSF proteome. Increased expression of EGFR is observed in fibroblasts deficient in PS/gamma-secretase activity or APP expression [88]. Further, studies also indicate role of PS1 in trafficking and turnover of EGFR as well as perturbed endosomal-lysosomal trafficking in cell cycle control and Alzheimer disease and suggest potential pathogenic effects of elevated EGFR [89]. "
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    • "Othermechanismsofsignaltransductionhavealsobeen proposed.APPhasbeensuggestedtoactivategenetranscriptioninasimilarmannertoNotch ,whichsignalsthrough thec-secretase-mediatedreleaseoftheNotchintracellular domain.Thisdomaintranslocatestothenucleusand activatesgenetranscription.TheAICDfragmentofAPP hasalsobeenreportedtotranslocatetothenucleus(Cupers etal.2001;GaoandPimplikar2001).NormallyAICDis pronetodegradation(Kimberlyetal.2001).However, AICDcanbeboundbyFe65,whichbindstotheYENPTY motifthroughitsphosphotyrosine-bindingdomain(Fiore etal.1995).Fe65bindingmayhelptostabiliseAICD (Kimberlyetal.2001).Aftertranslocatingtothenucleus,the Fe65-boundAICDhasbeenreportedtoformatranscrip- tionallyactivecomplexincombinationwithTat-interactive protein60(Tip60),whichisahistoneacetyltransferase(Cao andSudhof2001;GaoandPimplikar2001).Anumberof targetgeneshavebeenreportedforAICD.Thesegenes includeKAI1(Baeketal.2002),APP,BACE,Tip60(von Rotzetal.2004),glycogensynthasekinase-3b(Kimetal. 2003),EGFR(Zhangetal.2007),p53(Checleretal.2007), neprilysin(Belyaevetal.2009)andlow-densitylipoprotein- receptorrelatedfamilyproteins(Liuetal.2007). "
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    • "Maintenance of mouse embryonic fibroblast (MEF) cells derived from APP/APLP2 double knockout and control mice [22], phenochromocytoma PC12 cells [17], and primary neuronal cultures derived from postnatal day 0 mice or embryonic day 17 rat embryos [23], has been previously described. MEF cells were transiently transfected with APP, TrkA, and/or p75NTR plasmids using Lipofectamine 2000 (Invitrogen). "
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