Abstract
A common arginine to proline polymorphism is harboured at codon 72 of the human p53 gene. In this investigation, we found that fibroblasts and lymphocytes isolated from arginine allele homozygote centenarians and sexagenarians (Arg+) undergo an oxidative-stress-induced apoptosis at a higher extent than cells obtained from proline allele carriers (Pro+). At variance, the difference in apoptosis susceptibility between Arg+ and Pro+ is not significant when cells from 30-year-old people are studied. Further, we found that Arg+ and Pro+ cells from centenarians differ in the constitutive levels of p53 protein and p53/MDM2 complex, as well as in the levels of oxidative stress-induced p53/Bcl-xL complex and mitochondria-localised p53. Consistently, all these differences are less evident in cells from 30-year-old people. Finally, we investigated the in vivo functional relevance of the p53 codon 72 genotype in a group of old patients (66–99 years of age) affected by acute myocardial ischaemia, a clinical condition in which in vivo cell death occurs. We found that Arg+ patients show increased levels of Troponin I and CK-MB, two serum markers that correlate with the extent of the ischaemic damage in comparison to Pro+ patients. In conclusion, these data suggest that p53 codon 72 polymorphism contributes to a genetically determined variability in apoptotic susceptibility among old people, which has a potentially relevant role in the context of an age-related pathologic condition, such as myocardial ischaemia.
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Abbreviations
- <2c cells:
-
cells with hypodiploic DNA content
- ACS:
-
acute coronary syndrome
- Arg+:
-
arginine/arginine carriers
- CCU:
-
Coronary Care Unit
- CK-MB:
-
creatine kinase, MB fraction
- CRP:
-
C-reactive protein
- dc:
-
detached cells
- DFs:
-
dermal fibroblasts
- dRib:
-
2-deoxy-D-ribose
- e.s.l.:
-
equal sample loading
- HDL:
-
high-density lipoprotein
- LCLs:
-
lymphoblastoid cells lines
- NQw-MI:
-
non-Q wave myocardial infarction
- p53Arg:
-
p53 codon 72 arginine allele
- p53Pro:
-
p53 codon 72 proline allele
- PBMCs:
-
peripheral blood mononuclear cells
- PI:
-
propidium iodide
- P-p53ser 15:
-
serine 15-phosphorylated p53
- Pro+:
-
proline/proline or proline/arginine carriers
- pTet-On:
-
tetracycline inducible plasmid
- pTRE:
-
tetracycline responsive element plasmid
- Qw-MI:
-
Q-wave myocardial infarction
- S.D.:
-
standard deviation
- s.e.m.:
-
standard error of the mean
- UA:
-
unstable angina
- ΔΨdim cells:
-
cells with depolarised mitochondria
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Acknowledgements
This work was supported by AIRC (Associazione Italiana Ricerca sul Cancro) Grant, EU (European Union) Grants ‘FUNCTIONAGE’, ‘ECHA’, ‘T-CIA’, and ex 40% MIUR, (Italian Ministry of University) Grant, and FIRB (Fondi Istituzionali per la Ricerca di Base) and Ministero della Salute (Italian Ministry of Health) Finalizzate 2003 Grant to CF.
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Bonafé, M., Salvioli, S., Barbi, C. et al. The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death. Cell Death Differ 11, 962–973 (2004). https://doi.org/10.1038/sj.cdd.4401415
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DOI: https://doi.org/10.1038/sj.cdd.4401415
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