Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53.
The cellular function of p53 is complex. It is well known that p53 plays a key role in cellular response to DNA damage. Moreover, p53 was implicated in cellular senescence, and it was demonstrated that p53 undergoes modification in senescent cells. However, it is not known how these modifications affect the ability of senescent cells to respond to DNA damage. To address this question, we studied the responses of cultured young and old normal diploid human fibroblasts to a variety of genotoxic stresses. Young fibroblasts were able to undergo p53-dependent and p53-independent apoptosis. In contrast, senescent fibroblasts were unable to undergo p53-dependent apoptosis, whereas p53-independent apoptosis was only slightly reduced. Interestingly, instead of undergoing p53-dependent apoptosis, senescent fibroblasts underwent necrosis. Furthermore, we found that old cells were unable to stabilize p53 in response to DNA damage. Exogenous expression or stabilization of p53 with proteasome inhibitors in old fibroblasts restored their ability to undergo apoptosis. Our results suggest that stabilization of p53 in response to DNA damage is impaired in old fibroblasts, resulting in induction of necrosis. The role of this phenomenon in normal aging and anticancer therapy is discussed.
Seluanov
A
A
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel. Seluanov_Andrei@hotmail.com
Gorbunova
V
V
Falcovitz
A
A
Sigal
A
A
Milyavsky
M
M
Zurer
I
I
Shohat
G
G
Goldfinger
N
N
Rotter
V
V
D000165:Acridine Orange / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002469:Cell Separation; D002478:Cells, Cultured; D016922:Cellular Senescence; D002945:Cisplatin / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D004249:DNA Damage; D003609:Dactinomycin / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000528:radiation effects; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009336:Necrosis; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*; D014466:Ultraviolet Rays
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D009097:Multienzyme Complexes; D019384:Nucleic Acid Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D005047:Etoposide; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000165:Acridine Orange; D002945:Cisplatin