p53 codon 72 alleles influence the response to anticancer drugs in cells from aged people by regulating the cell cycle inhibitor p21WAF1.
A common polymorphism at codon 72 in p53 gene leads to an arginine to proline aminoacidic substitution which affects in an age-dependent manner the susceptibility of cells to undergo apoptosis after oxidative stress. Here we report that dermal fibroblasts from Proline allele carriers (Pro+) display a higher expression of p21WAF1 gene, in both basal conditions and after treatment with doxorubicin or camptothecin. This phenomenon is accompanied by a lower susceptibility of Pro+ cells to undergo apoptosis, a lower capability to over cross G1-S transition and an increased propensity to express markers of cell senescence, with respect to fibroblasts from Arginine homozygotes (Pro-). All these phenomena are particularly evident in cells from centenarians. We conclude that the functional difference between the two p53 codon 72 alleles exerts a broad impact on the capability of cell from aged people to respond to stressors such as cytotoxic drugs.
Salvioli
Stefano
S
Department of Experimental Pathology, University of Bologna, Bologna, Italy. stefano.salvioli2@unibo.it
Bonafé
Massimiliano
M
Barbi
Cristiana
C
Storci
Gianluca
G
Trapassi
Chiara
C
Tocco
Francesca
F
Gravina
Silvia
S
Rossi
Matteo
M
Tiberi
Luca
L
Mondello
Chiara
C
Monti
Daniela
D
Franceschi
Claudio
C
D000328:Adult; D000367:Age Factors; D000369:Aged, 80 and over; D000375:Aging; D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001120:Arginine / Q000737:chemistry; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D016923:Cell Death; D002469:Cell Separation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003062:Codon; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006720:Homozygote; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009841:Oligonucleotides / Q000737:chemistry; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D011392:Proline / Q000737:chemistry; D011419:Propidium / Q000494:pharmacology; D020033:Protein Isoforms; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D003062:Codon; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009841:Oligonucleotides; D020033:Protein Isoforms; D011419:Propidium; D001120:Arginine; D011392:Proline; D008156:Luciferases; D001616:beta-Galactosidase; D001973:Bromodeoxyuridine