Role of a mutant p53 protein in apoptosis: characterization of a function independent of transcriptional trans-activation.
Wild-type (wt) tumor suppressor p53 has been implicated in cellular radiosensitivity, mediated by its role in apoptosis and growth arrest. Intriguingly, it was observed that the temperature sensitive (ts) mutant p53val135 protein functions as a positive modulator of cellular radiosensitivity, as evident from acceleration of irradiation-induced apoptosis of M1p53ts (p53val135) cells at the non-permissive temperature; this effect was correlated with acceleration of exit from the G2 checkpoint of the cell cycle. In this work it is shown that the ability of mutant p53val135 to accelerate irradiation-induced apoptosis, at the non-permissive temperature, was devoid of transcriptional trans-activation of p53 target genes. In contrast, the apoptotic function of wt p53val135 was observed to include components which are both dependent and independent of transcriptional trans-activation. Taken together, these observations suggest that mutant p53val135 protein retains the apoptotic component of wt p53 that is devoid of transcriptional trans-activation, and that, although this activity is insufficient to induce apoptosis on its own, it can cooperate to accelerate DNA damage-induced cell death. The results of this work contribute to a better understanding of the complexity of the apoptotic response elicited by wt p53, and highlight the potential role of mutant p53 proteins, as well as trans-activation independent apoptosis, in tumor suppression by irradiation therapy.
Guillouf
C
C
Fels Institute for Cancer Research and Molecular Biology and Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Rosselli
F
F
Sjin
R T
RT
Moustacchi
E
E
Hoffman
B
B
Liebermann
D A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D051379:Mice; D016296:Mutagenesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D003513:Cycloheximide