title: Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively.
abstract: Presenilin 1 (PS1) has been implicated in apoptosis; however, its mechanism remains elusive. We report that PS1-induced apoptosis was associated with cellular FLICE-like inhibitory protein (c-FLIP) turnover and that γ-secretase inhibitor blocked c-FLIP turnover and also partially blocked PS1-induced apoptosis. A complete inhibition of PS1-induced apoptosis was achieved by knockdown of PS1-associated protein (PSAP), a mitochondrial proapoptotic protein that forms a complex with Bax upon induction of apoptosis, in the presence of γ-secretase inhibitor. PS1-induced apoptosis was partially inhibited by knockdown of caspase-8, Fas-associated protein with death domain (FADD), or Bid. However, knockdown of Bax or overexpression of Bcl-2 resulted in complete inhibition of PS1-induced apoptosis. These data suggest that PS1 induces apoptosis through two pathways: the γ-secretase-dependent pathway mediated by turnover of c-FLIP and the γ-secretase-independent pathway mediated by PSAP-Bax complex formation. These two pathways converge on Bax to activate mitochondria-dependent apoptosis. These findings provide new insight into the mechanisms by which PS1 is involved in apoptosis and the mechanism by which PS1 exerts its pathogenic effects. In addition, our results suggest that PS2 induces apoptosis through a pathway that is different from that of PS1.
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, and.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zeng
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, and the Department of Comparative and Experimental Medicine, University of Tennessee, Knoxville, Tennessee 37996 and.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, and.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: the Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Xu
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, and.
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Cui
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, and xmx@utk.edu.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000096:biosynthesis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D049231:Saposins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; C483345:PSAP protein, human; D053764:Presenilin-1; D019253:Proto-Oncogene Proteins c-bcl-2; D049231:Saposins; D051028:bcl-2-Associated X Protein; D053829:Amyloid Precursor Protein Secretases; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Alzheimer disease; apoptosis; caspase; cell death; mitochondrial apoptosis; presenilin