Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage.
PS2, the chromosome 1 familial Alzheimer's disease gene, has been shown to be involved in programmed cell death by three complementary experimental approaches. Reduction of PS2 protein levels by antisense RNA protects from apoptosis, whereas overexpression of an Alzheimer's PS2 mutant increases cell death induced by several stimuli. In addition, ALG-3, a truncated PS2 cDNA, encodes an artificial COOH-terminal PS2 segment that dominantly inhibits apoptosis. Here we describe a physiological COOH-terminal PS2 polypeptide (PS2s, Met298-Ile448) generated by both an alternative PS2 transcript and proteolytic cleavage. We find that PS2s protects transfected cells from Fas- and tumor necrosis factor alpha (TNFalpha)-induced apoptosis. Furthermore, a similar anti-apoptotic COOH-terminal PS2 polypeptide (PS2Ccas) is generated by caspase-3 cleavage at Asp329. These results suggest that caspase-3 not only activates pro-apoptotic substrates but also generates a negative feedback signal in which PS2Ccas antagonizes the progression of cell death. Thus, whereas PS2 is required for apoptosis, PS2s and PS2Ccas oppose this process, and the balance between PS2 and these COOH-terminal fragments may dictate the cell fate.
Vito
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T Cell Molecular Biology Unit, Laboratory of Cellular and Molecular Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ghayur
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D'Adamio
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D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D019556:COS Cells; D053148:Caspase 3; D020169:Caspases; D016384:Consensus Sequence; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D053222:Fas Ligand Protein; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D053766:Presenilin-2; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004792:Enzyme Precursors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases