Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most mutations in amyloid precursor proteins (APPs) linked to early onset familial Alzheimer's disease (FAD) increase the production of amyloid-beta peptides ending at residue 42 (Abeta42), which are released from APP by beta- and gamma-secretase cleavage. Stably transfected cells expressing wild-type human APP (APP(WT)) were more resistant to apoptosis-inducing treatments than cells expressing FAD-mutant human APP (APP(FAD)). Preventing Abeta42 production with an M596I mutation (beta-), which blocks beta-secretase cleavage of APP, or by treatment with a gamma-secretase inhibitor increased the resistance of APP(FAD)-expressing cells to apoptosis. Exposing hAPP(FAD/beta-) cells to exogenous Abeta42 or conditioned medium from Abeta42-producing APP(FAD) cells did not diminish their resistance to apoptosis. Preventing APP from entering the distal secretory pathway, where most Abeta peptides are generated, by retaining APP in the endoplasmic reticulum (ER)/intermediate compartment (IC) increased the resistance of APP(FAD)-expressing cells to apoptosis and did not alter the resistance of APP(WT)-expressing cells. p53-mediated gene transactivation after apoptosis-inducing treatments was much stronger in APP(FAD) cells than in hAPP(WT) or hAPP(FAD/beta-) cells. In contrast, upon induction of ER stress, cells expressing APP(FAD), hAPP(FAD/beta-), or APP(WT) had comparable levels of glucose-regulated protein-78 mRNA, an unfolded protein response indicator. We conclude that Abeta, especially intracellular Abeta, counteracts the antiapoptotic function of its precursor protein and predisposes cells to p53-mediated, and possibly other, proapoptotic pathways.
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PMID:Intracellularly generated amyloid-beta peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells. 1558 3

Here we show that human embryonic kidney (HEK) cells stably transfected with amyloid precursor protein (HEK-APP), expressed a conformational mutant-like and transcriptionally inactive p53 isoform, and turned out to be less sensitive to the cytotoxin doxorubicin in comparison with untransfected cells. Treatment of HEK-APP cells with gamma- and beta-secretase inhibitors prevented generation of unfolded, mutant-like p53 isoform and made the cells vulnerable to doxorubicin as untransfected cells. Changes in p53 conformational state and reduced sensitivity to doxorubicin were also found in untransfected HEK cells after exposure to nanomolar concentrations of beta-amyloid (Abeta) and these effects were antagonized by vitamin E. The modulator effects of Abeta on p53 conformational state were, at least in part, due to the intracellular peptides as (i) treatment of HEK-APP cells with an antibody that sequestered extracellular Abeta did not modify the capability of the cells to express the mutant-like p53 isoform; (ii) in the presence of 1% serum exogenous Abeta peptide crossed the plasma membrane, as demonstrated by confocal analysis and ELISA, and induced p53 conformational change; and (iii) in the presence of 10% serum Abeta did not enter the cells and consequently did not influence the p53 conformational state.
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PMID:Over-expression of amyloid precursor protein in HEK cells alters p53 conformational state and protects against doxorubicin. 1760 41

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.
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PMID:Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors. 1927 51