title: TMP21 regulates Abeta production but does not affect caspase-3, p53, and neprilysin.
abstract: The presenilin (PS)-dependent gamma-secretase activity refers to a high molecular mass-complex including, besides PS1 or PS2, three other proteins recently identified, namely nicastrin, Aph-1, and Pen-2. This proteolytic complex has been shown to contribute to both gamma- and epsilon-cleavages of the beta-amyloid precursor protein (betaAPP), thereby generating beta-amyloid peptides (Abeta) and the APP intracellular domain (AICD), respectively. TMP21, a member of the p24 cargo protein family, was recently shown to interact with PS complexes. Interestingly, TMP21 modulates gamma-secretase-mediated Abeta production but does not regulate epsilon-secretase-derived AICD formation [F. Chen, H. Hasegawa, G. Schmitt-ulms, T. Kawarai, C. Bohm, T. Katayama, Y. Gu, N. Sanjo, M. Glista, E. Rogaeva, Y. Wakutami, R. Pardossi-Piquard, X. Ruan, A. Tandon, F. Checler, P. Marambaud, K. Hansen, D. Westaway, P. St. George-Hyslop, P. Fraser, TMP21 is a presenilin complex component that modulates gamma- but not epsilon-secretase activities, Nature 440 (2006) 1208-1212]. Here we investigate the functional incidence of the over-expression or depletion of TMP21 on both intracellular and secreted Abeta recoveries and AICD-associated phenotypes. First we confirm that TMP21 depletion yields increased levels of secreted Abeta40. However, we demonstrate that both staurosporine-stimulated caspase-3 activation, p53 and neprilysin expression and activity were not affected by TMP21 over-expression or depletion. Overall, our functional data further reinforce the view that TMP21 behaves as a regulator of gamma- but not epsilon-cleavages generated by PS-dependent gamma-secretase complex.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097, Centre National de la Recherche Scientifique-Université Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 Route des Lucioles, 06560 Valbonne, France.
authors.forename: Virginia
authors.initials: V
authors.lastname: Dolcini
authors.forename: Julie
authors.initials: J
authors.lastname: Dunys
authors.forename: Jean
authors.initials: J
authors.lastname: Sevalle
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.forename: Marie-Victoire
authors.initials: MV
authors.lastname: Guillot-Sestier
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D029543:Nucleocytoplasmic Transport Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C484395:TMED10 protein, human; D016159:Tumor Suppressor Protein p53; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D015260:Neprilysin