HIPK2-induced p53Ser46 phosphorylation activates the KILLER/DR5-mediated caspase-8 extrinsic apoptotic pathway

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The p53 oncosuppressor is the most common altered gene in human cancers, and its regulation in controlling cell cycle and apoptosis is central in the problem of human tumorigenesis.¹ In response to DNA damage, p53 is activated mostly at the post-translational level by complex series of modifications, including phosphorylation and acetylation, leading to control cell life and death.^{2, 3} Apoptosis has recently been suggested to be a major contribution to p53-mediated suppression of tumor formation, and resistance to apoptosis is one of the major hurdles in the treatment of cancer.⁴ The mechanisms by which p53 accomplishes its apoptotic function have been studied and involve activation of the mitochondrial pathway, the death receptor pathway, and cleavage of downstream caspases.⁵ Numerous publications have recently described the importance of p53 transcriptional regulation of components of both extrinsic and intrinsic apoptotic pathway including Bax, p53AIP1, Noxa, PUMA, Fas/Apo1, KILLER/DR5, and PERP, although cells that have engaged p53-dependent apoptosis typically follow the intrinsic cell death pathway.⁵ Several genes may be recruited simultaneously by p53 within the same cell, probably acting additively or synergistically, whereas others may be more cell type-restricted with regard to their requirement for p53-mediated apoptosis. Either way, it has been suggested that the choice of p53 between life and death may be dictated by its ability to switch on preferentially particular subsets of genes. The molecular basis for the different activation of particular subsets of target genes is not fully understood. Most certainly, multiple molecular mechanisms contribute to p53's target selectivity. There is now ample evidence that covalent modifications on p53, possibly through conformational changes, which alter directly its DNA-binding specificity, may play a critical role in its target genes preference. However, which phosphorylation sites may be modified after DNA damage to induce the different apoptotic pathways has only recently begun to be addressed.

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