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

Abstract

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.

hAda3 regulates p14ARF-induced p53 acetylation and senescence

“…We found decreased Ac-K382-p53 levels in senescent hTERT-MEC by day 12 post-p14ARF infection, suggesting that after senescence is established persistent p53 acetylation is not required. It is in agreement with observation that cells with inducible p53 exhibit irreversible growth arrest after p53 expression ceased (Sugrue et al, 1997).…”

Cell cycle arrest is sufficient for p53-mediated tumor regression

“…20,21 Thus, in the H358 cell line, expression of p53 might restore the senescence pathway activated by the Ras oncogene. 22,23 As previously shown, 23 p53-mediated senescence is associated with G 0 /G 1 and G 2 /M cell cycle arrest, p21 induction and down-regulation of cyclin A, cyclin B1 and cdc2. Furthermore, down-regulation of hTERT expression, a key enzyme in the control of the telomerase activity and the senescence process, 24,25 is not observed in our model, in accordance with observations of a telomere-independent clock in cells expressing oncogenic RAS.…”

P21 gene expression as an indicator for the activity of adenovirus-p53 gene therapy in non-small cell lung cancer patients

“…11 It is noteworthy that in phase I, samples from patients 2 and 3, who had the strongest increase in p21 gene expression, were shown previously to contain the p53 transgene by an independent PCR on cDNA from the same biopsy 6 (see also Table 1). Moreover, at the follow-up at 28 days posttreatment, both patients showed stabilization of the injected tumor, as opposed to patients 1, 4, and 5, who were negative for both p53 transgene expression and p21 increase and had rapidly progressing tumors.…”