p53 has a key role in the maintenance of the genetic stability and, thus, in preventing tumour development. The current model is that the p53-dependent responses are solely driven by p53α. The uncovering that the TP53 gene physiologically expresses several p53 isoforms, challenges this paradigm. According to the data gathered about p53 isoforms in the past ten years, we hypothesise that the so-called p53 is a multi-protein system composed by the twelve isoforms and that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the co-expressed p53 isoforms. Here, we report that the TP53 gene always co-expresses several p53 protein isoforms in cells, tumour tissues and also in normal human tissues. Physiologically, the HPV E6 protein differentially regulates the expression of all p53 isoforms to command replication. Differentially modulating isoforms expression using siRNAs, without changing extra-cellular signals, alters the cell-fate outcome. Furthermore, we establish that the p53 pathway is still active in cell lines devoid of canonical p53α expression, but retaining expression of other isoforms. Mechanistically, we demonstrate that, depending on post-translational modifications, the isoforms co-expressed in a given cell type, oligomerise together and regulate target-gene transactivation in a promoter-dependent manner. Altogether, this study shows that p53 functions as a multi-protein system that is functional in the absence of canonical p53α. The cellular content in p53 isoforms defines the cell response. The isoforms oligomerise together, depending on post-translational modifications, to finely tune target-gene expression in a promoter-dependent manner. These data indicate that the p53 isoforms would compose a cellular code. Cracking “the p53 isoforms’ code” will, therefore, enable to define cell responses and to develop new therapeutic strategies.
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