The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis.
In cells undergoing apoptosis, a 22-amino-acid presenilin-2-loop peptide (PS2-LP, amino acids 308-329 in presenilin-2) is generated through cleavage of the carboxyl-terminal fragment of presenilin-2 by caspase-3. The impact of PS2-LP on the progression of apoptosis, however, is not known. Here we show that PS2-LP is a potent inducer of the mitochondrial-dependent cell death pathway when transduced as a fusion protein with HIV-TAT. Biochemical and functional studies demonstrate that TAT-PS2-LP can interact with the inositol 1,4,5-trisphosphate receptor and activate Ca(2+) release from the endoplasmic reticulum. These results indicate that PS2-LP-mediated alteration of intracellular Ca(2+) homeostasis may be linked to the acceleration of apoptosis. Therefore, targeting the function of PS2-LP could provide a useful therapeutic tool for the treatment of cancer and degenerative diseases.
Cai
Chuanxi
C
Department of Physiology and Biophysics, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Lin
Peihui
P
Cheung
King-Ho
KH
Li
Na
N
Levchook
Christina
C
Pan
Zui
Z
Ferrante
Christopher
C
Boulianne
Gabrielle L
GL
Foskett
J Kevin
JK
Danielpour
David
D
Ma
Jianjie
J
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006706:Homeostasis; D007313:Insecta; D008565:Membrane Proteins / Q000737:chemistry*; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D053766:Presenilin-2; D051381:Rats
D008565:Membrane Proteins; D010455:Peptides; D053766:Presenilin-2; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium