title: Sox2 functionally interacts with βAPP, the βAPP intracellular domain and ADAM10 at a transcriptional level in human cells.
abstract: Sox2 (SRY (Sex-determining region Y)-related high mobility group (HMG) box 2) is a transcription factor that serves key roles in controlling the balance between stem cells maintenance and commitment to differentiated lineages throughout the lifetime. Importantly, Sox2 deficiency results in early embryonic lethality whereas the down-regulation of Sox2 expression triggers neurodegeneration in the adult mouse brain. Moreover, Sox2 is decreased in the brain of Alzheimer's disease (AD) patients and co localizes with the β-amyloid precursor protein (βAPP) in stem cells. Here we report the existence of functional interactions between Sox2 and βAPP, the βAPP intracellular domain AICD50 and the α-secretase ADAM10 in human cells. We first show, as observed in embryonic stem cells, that βAPP overexpression in HEK293 cells results in an increase of Sox2 immunoreactivity and we further establish the transcriptional nature of this pathway. Moreover, overexpression of the pro-apoptotic C-terminal βAPP-derived AICD50 metabolite leads to the down-regulation of Sox2 transcription whereas the pharmacological inhibition of endogenous AICD production increases Sox2 expression in both HEK293 and SH-SY5Y cell lines. In addition, we demonstrate that Sox2 is a potent activator of the non amyloidogenic processing of βAPP as shown by the Sox2-dependent augmentation of ADAM10 catalytic activity, immunoreactivity, promoter transactivation and mRNA levels with no modification of the activity and the expression of the β-secretase BACE1. Finally, the fact that γ-secretase inhibition induces an increase of ADAM10 protein levels in SH-SY5Y cells further supports the occurrence of functional AICD/Sox2/ADAM10 interactions. Altogether, our study identifies and characterizes new functional cross-talks between Sox2 and proteins involved in AD, thereby adding support to the view that Sox2 likely behaves as a protective factor during the development of this neurodegenerative disease.
authors.affiliation: The Research Center for Neuroscience, Mahidol University, Nakhon Pathom 73170, Thailand; Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand.
authors.forename: G
authors.initials: G
authors.lastname: Sarlak
authors.affiliation: Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand.
authors.forename: H H
authors.initials: HH
authors.lastname: Htoo
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR5247 CNRS/Université de Montpellier/ENSCM, Faculté de Pharmacie, 34093 Montpellier Cedex 5, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Hernandez
authors.affiliation: Department of Microbiology, Shimane University, Faculty of Medicine, 89-1 Enya, Izumo City, Shimane 693-8501, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Iizasa
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire CNRS/Université de Nice-Sophia-Antipolis, Equipe labellisée LABEX DistALZ, 06560 Valbonne, France.
authors.forename: F
authors.initials: F
authors.lastname: Checler
authors.affiliation: Division of Psychiatry Research and Psychogeriatric Medicine, University of Zurich, CH-8008 Zurich, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Konietzko
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.affiliation: The Research Center for Neuroscience, Mahidol University, Nakhon Pathom 73170, Thailand; Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand; Centre National de la Recherche Scientifique, 75016 Paris, France. Electronic address: bruno.vin@mahidol.ac.th.
authors.forename: B
authors.initials: B
authors.lastname: Vincent
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D065840:Protective Factors; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM10; AICD; Alzheimer; Sox2; transcription; βAPP