A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function.
The tumor suppressor p53 is an inducer of cell cycle arrest and programmed cell death (apoptosis). The ability of p53 to induce cell cycle arrest is linked to its ability to induce transcription of genes such as the cyclin-dependent kinase inhibitor p21. However, the dependence of p53-mediated apoptosis on transcriptional activation remains controversial. Ectopic expression of a temperature-sensitive (ts) p53 allele induced expression of p53 target genes and elicited both G1 and G2/M cell cycle arrest upon shift to the permissive temperature. Ectopic expression of the same ts p53 allele with two additional point mutations (Gln22, Ser23) that abolish p53-transcriptional activation did not induce p53 target genes and G1 nor G2/M cell cycle arrest. In HCT116 colon carcinoma cells ectopic expression of wild type p53 does not elicit apoptosis whereas p53 mutant deficient in trans-activation induces apoptosis. The ability of wild type p53 to induce apoptosis is restored in HCT116 cells that are null for p21. However, the trans-activation deficient mutant of p53 is still more potent mediator of apoptosis than wild type p53 in the p21 null cells. Although the ability of Gln22,Ser23 to trans-activate p53 target genes is diminished, it retains the ability to repress Bcl-2 expression. Thus, we conclude that while ectopic expression of wild type p53 can induce both G1 and G2/M arrest, in a p21 dependent manner, without apoptosis, a p53 mutant defective in trans-activation elicits apoptosis without inducing cell cycle arrest. Further, the anti-apoptotic function of p53 is dependent on trans-activation and is linked to cell cycle arrest. The results strongly suggest that the trans-activation deficient mutant is a more potent inducer of apoptosis because it lost its anti-apoptotic function and retains its ability to repress pro-apoptotic genes such as Bcl-2. Taken together, the results imply that employing a trans-activation deficient p53 in gene therapy approaches or the use of drugs that convert mutant p53 to a trans-activation-independent mediator of apoptosis may be much more efficient therapeutic approaches than current approaches that employ wild type p53.
Kokontis
J M
JM
The Ben May Institute for Cancer Research, University of Chicago, IL 60637, USA.
Wagner
A J
AJ
O'Leary
M
M
Liao
S
S
Hay
N
N
D017209:Apoptosis / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006801:Humans; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein