Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53

The p53 tumor suppressor gene has been shown to play an important role in determining cell fate. Overexpression of wild-type p53 in tumor cells has been shown to lead to growth arrest or apoptosis. Previous studies in fibroblasts have provided indirect evidence for a link between p53 and senescence. Here we show, using an inducible p53 expression system, that wild-type p53 overexpression in EJ bladder carcinoma cells, which have lost functional p53, triggers the rapid onset of G(1) and G(2)/M growth arrest associated with p21 up-regulation and repression of mitotic cyclins (cyclin A and B) and cdc2. Growth arrest in response to p53 induction became irreversible within 48-72 h, with cells exhibiting morphological features as well as specific biochemical and ultrastructural markers of the senescent phenotype. These findings provide direct evidence that p53 overexpression can activate the rapid onset of senescence in tumor cells.

p53肿瘤抑制基因（p53 tumor suppressor gene）业已证实其在细胞命运决定过程中发挥关键作用。在肿瘤细胞中过表达野生型p53，已被证实可引发生长停滞或细胞凋亡。此前针对成纤维细胞的研究，已为p53与细胞衰老之间的关联提供了间接证据。本研究借助可诱导型p53表达系统，证实于丧失功能性p53的EJ膀胱癌细胞中过表达野生型p53，会触发G₁期与G₂/M期的快速生长停滞，该过程伴随p21的上调，以及有丝分裂周期蛋白（cyclin A与B）及cdc2的表达抑制。在p53诱导后的48至72小时内，细胞的生长停滞状态会转为不可逆，此时细胞将呈现衰老表型的形态学特征、特异性生化标志物与超微结构标志物。上述发现为p53过表达可激活肿瘤细胞的快速衰老进程提供了直接实验证据。