Seluanov A, Gorbunova V, Falcovitz A, Sigal A, Milyavsky M, Zurer I, Shohat G, Goldfinger N, Rotter V
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
Mol Cell Biol. 2001 Mar;21(5):1552-64. doi: 10.1128/MCB.21.5.1552-1564.2001.
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.
p53的细胞功能很复杂。众所周知，p53在细胞对DNA损伤的反应中起关键作用。此外，p53与细胞衰老有关，并且已证明p53在衰老细胞中会发生修饰。然而，尚不清楚这些修饰如何影响衰老细胞对DNA损伤的反应能力。为了解决这个问题，我们研究了培养的年轻和老年正常二倍体人成纤维细胞对各种基因毒性应激的反应。年轻的成纤维细胞能够经历p53依赖性和p53非依赖性凋亡。相比之下，衰老的成纤维细胞无法经历p53依赖性凋亡，而p53非依赖性凋亡仅略有减少。有趣的是，衰老的成纤维细胞没有经历p53依赖性凋亡，而是发生了坏死。此外，我们发现衰老细胞在DNA损伤时无法稳定p53。在衰老的成纤维细胞中通过蛋白酶体抑制剂外源表达或稳定p53可恢复其凋亡能力。我们的结果表明，衰老的成纤维细胞对DNA损伤时p53的稳定受到损害，导致坏死的诱导。讨论了这种现象在正常衰老和抗癌治疗中的作用。
