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We recently reported that the human p53 gene encodes at least nine different p53 isoforms, two of which (p53β and Δ133p53) can modulate p53 transcriptional activity and apoptosis. In the present study, we aimed to investigate the regulation of Δ133p53 isoform expression and the physiological role of Δ133p53 in modulating p53 activities. We report that in response to genotoxic stress, p53 transactivates directly the human p53 internal promoter inducing Δ133p53 protein expression, which by differentially modulating p53 target gene expression prevents p53-mediated apoptosis without inhibiting cell cycle arrest. This indicates that Δ133p53 does not simply act at physiological level in a dominant-negative manner towards any p53 targets, but rather modulates p53 transcriptional activity in a promoter and stress-dependent manner. Hence, we have established a novel feedback pathway that modulates the p53 response, which might have an impact on p53 tumour suppressor activity. These observations may provide some explanations for the difficulties in many clinical studies of associating p53 status with cancer treatment and clinical outcome. Therefore, it would be interesting to determine whether Δ133p53 expression is associated with tumour markers, clinical outcome and cancer treatment in human cancers. |
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