Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.
 

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05-19-09 09:41 AM
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Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.
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Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.

J Alzheimers Dis. 2009 Mar;16(3):565-75

Authors: Ma L, Ohyagi Y, Miyoshi K, Sakae N, Motomura K, Taniwaki T, Furuya H, Takeda K, Tabira T, Kira J

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.

PMID: 19276551 [PubMed - indexed for MEDLINE]