Dissection of the genetic programs of p53-mediated G1 growth arrest and apoptosis: blocking p53-induced apoptosis unmasks G1 arrest (original) (raw)
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Specific loss of apoptotic but not cell - cycle arrest function in a human tumor derived p53 mutant
1996
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 p53 tumour suppressor gene: a mediator of a G1 growth arrest and of apoptosis
Experientia, 1996
The turn0ur suppressor gene p53 plays a major role in the protection of cells from DNA damage. Activation of the protein in response to irradiation or genotoxic agents, and possibly by other signals, results in growth arrest at the G1 phase of the cell cycle or in apoptosis. While it has been shown that the ability of p53 to function as a sequence-specific transcriptional activator is necessary for the induction of growth arrest, the meChanism of p53-mediated apoptosis is not yet clear. It appears that under some conditions activation of the G1 checkpoint will prevent apoptosis, but the cellular environment may alter the result of p53 activation towards cell death, p53 may also directly induce apoptosis through several pathways, which may be transcriptionally dependent or independent. The outcome -a G1 arrest or apoptosis -will depend on a complex network of regulatory signals.
p53-mediated cell death: relationship to cell cycle control
Molecular and cellular biology, 1993
M1 clone S6 myeloid leukemic cells do not express detectable p53 protein. When stably transfected with a temperature-sensitive mutant of p53, these cells undergo rapid cell death upon induction of wild-type (wt) p53 activity at the permissive temperature. This process has features of apoptosis. In a number of other cell systems, wt p53 activation has been shown to induce a growth arrest. Yet, wt 53 fails to induce a measurable growth arrest in M1 cells, and cell cycle progression proceeds while viability is being lost. There exists, however, a relationship between the cell cycle and p53-mediated death, and cells in G1 appear to be preferentially susceptible to the death-inducing activity of wt p53. In addition, p53-mediated M1 cell death can be inhibited by interleukin-6. The effect of the cytokine is specific to p53-mediated death, since apoptosis elicited by serum deprivation is refractory to interleukin-6. Our data imply that p53-mediated cell death is not dependent on the induct...
Toxicology Letters, 1998
The tumor suppressor gene p53 is a major player in the protection of cells from DNA damage. In the majority of human cancers, p53 is functionally inactivated--mostly by mutations but also by interaction with viral or cellular proteins. Wild-type p53 is involved in essential functions such as DNA repair, transcription, genomic stability, senescence, cell cycle control and apoptosis. It was shown to be a sequence-specific transcriptional activator, and this activity appears to be necessary to impose growth arrest. A major target gene which participates in p53-mediated growth arrest is p21/Waf1, an inhibitor of cyclin-dependent kinases. Whether or not transcriptional activation of target genes is required for p53-mediated apoptosis may depend on the cell type and external factors, and the mechanism of cell death induction is not clear yet. We have employed clones of the M1 myeloid leukemic cell line expressing a temperature-sensitive p53 mutant to study genes which are regulated during p53-induced apoptosis.
A mutant P53 can activate apoptosis through a mechanism distinct from those induced by wild type P53
Febs Letters, 2002
A common mutation in P53 protein occurs at amino acid residue 281 in the DNA binding domain (P53 glyð281Þ ), which results in loss of transcriptional regulation of P53 target genes and has been reported to gain pro-oncogenic functions. In the present study, we investigated the activity of P53 glyð281Þ in P53null PC3 human prostate cancer cells and found that the P53 glyð281Þ induced apoptosis as efficiently as the wild-type P53 (wtP53). However, in contrast to wtP53-induced apoptosis, the P53 glyð281Þ -induced apoptosis was insensitive to overexpression of bcl-2. Thus, our findings indicate that while a mutation in the DNA binding domain of p53 may result in a more oncogenic form of the protein, it may also paradoxically result in the 'gain' of a new, alternative pathway for apoptosis. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.