Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.
Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-beta42 (Abeta42) production as well as to promote apoptosis. We have recently reported that intracellular Abeta42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a beta-secretase inhibitor and gamma-secretase inhibitor decreased the intracellular Abeta levels in amyloid-beta protein precursor (AbetaPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AbetaPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Abeta and proteasome impairment.
Ma
Linqing
L
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ohyagi
Yasumasa
Y
Miyoshi
Katsue
K
Sakae
Nobutaka
N
Motomura
Kyoko
K
Taniwaki
Takayuki
T
Furuya
Hirokazu
H
Takeda
Kazuya
K
Tabira
Takeshi
T
Kira
Jun-ichi
J
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex