Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53

Abstract

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.

Senescence‐associated HSP60 expression in normal human skin fibroblasts

“…It seems that biochemical pathways leading to apoptosis, RS, and necrosis are connected by a network. In fact, senescent fibroblasts are resistant to programmed cell death stimuli, as the p53-induced one, and they die by necrosis when there is DNA damage (Seluanov et al, 2001). Soti and Csermely (2003), interestingly, have hypothesized that the balance between damaged proteins and chaperone availability is a key element in protein homeostasis during RS.…”

Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes

“…Upon senescence, at least some cell types become resistant to certain apoptotic signals (Wang et al, 1994;Linskens et al, 1995;Seluanov et al, 2001). This resistance to apoptosis may explain why senescent cells can accumulate in tissues with age (Dimri et al, 1995;Pendergrass et al, 1999;Choi et al, 2000;Ding et al, 2001;Paradis et al, 2001).…”

Failure of stress-induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts

“…The senescent phenotype is characterized by an increase in cell size, a distinct flat and enlarged morphology, 1,2 appearance of senescence-associated b-galactosidase (SA-bgalactosidase) activity, 3 hypo-responsiveness to growth factors, 4 resistance to apoptosis caused by stimuli such as UV, H 2 O 2 , staurosporine, etoposide and ceramide, 1,5,6 and broad changes in gene expression. 7 The mechanisms conferring resistance to stress-induced apoptosis in senescent human diploid fibroblasts have not been well studied.…”