Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant.

Abstract

The p53 tumor‐suppressor gene product is frequently inactivated in malignancies by point mutation. Although most tumor‐derived p53 mutants show loss of sequence specific transcriptional activation, some mutants have been identified which retain this activity. One such mutant, p53175P, is defective for the suppression of transformation in rodent cells, despite retaining the ability to suppress the growth of p53‐null human cells. We now demonstrate that p53175P can induce a cell‐cycle arrest in appropriate cell types but shows loss of apoptotic function. Our results therefore support a direct role of p53 transcriptional activation in mediating a cell‐cycle arrest and demonstrate that such activity is not sufficient for the full apoptotic response. These data suggest that either p53 can induce apoptosis through a transcriptionally independent mechanism, a function lost by p53175P, or that this mutant has specifically lost the ability to activate genes which contribute to cell death, despite activation of genes responsible for the G1 arrest. This dissociation of the cell‐cycle arrest and apoptotic activities of p53 indicates that inactivation of p53 apoptotic function without concomitant loss of growth inhibition can suffice to relieve p53‐dependent tumor‐suppression in vivo and thereby contribute to tumor development.

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models

“…Moreover, p53 haploinsufficieny affected tumorigeneic rates and the mdm2 hypomorphic mice were more resistant to tumours (Venkatachalam et al, 2001;Mendrysa et al, 2003). Secondly, although transient transfection studies such as those presented here have inherent limitations, the amount of transfected p53 was also shown by other investigators to correlate with the extent of its function, in many systems, including direct transfection of p53 alone, in combination with Mdm2 or Epstein-Barr virus-infection, in response to drug treatment or in cells that inducibly express varying amounts of p53 (Chen et al, 1996(Chen et al, , 1998Haupt et al, 1996;Rowan et al, 1996). Thus, it is evident that the levels of p53 in the cell can regulate the extent of its function, as is seen with human and mouse p53 in the MEFs.…”

Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene

“…Several investigators have shown that wt and mt p53 may regulate certain promoters in a specific cell type manner (Grinsberg et al, 1991;Santhanam et al, 1991;Chin et al, 1992;Subler et al, 1992;Mack et al, 1993;Haupt et al, 1996;Rowan et al, 1996); for example the PCNA promoter was not repressed by wt p53 in the study of Mack et al (1993) using cervical epithelium cells but the same promoter was repressed by wt p53 in the study of Subler et al (1992) using Hela or Vera cells. Rowan et al (1996) demonstrated that mutant p53 R175P could induce growth arrest but not apoptosis in Saos-2 and H1299 cells, whereas HeLa and H358 cells retained some apoptotic function after R175P expression. This cell-type effect may be due to specific cellular co-factors that couple with the activated form of p53, thus modulating its function.…”

Crippling p53 activities via knock-in mutations in mouse models

“…The p53R175P mutant shows a partial loss of function as it could transactivate p21, but fails to induce apoptosis (Crook et al, 1994;Ludwig et al, 1996;Rowan et al, 1996). To decipher the functional importance of cell-cycle arrest in absence of p53-dependent apoptosis on spontaneous tumorigenesis, mice carrying this mutation (172 in the mouse) were Crippling p53 activities via knock-in mutations T Iwakuma and G Lozano generated (p53R172P) .…”