A new p38 MAP kinase-regulated transcriptional coactivator that stimulates p53-dependent apoptosis

The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in stress-induced cell-fate decisions by orchestrating responses that go from cell-cycle arrest to apoptosis. We have identified a new p38 MAPK-regulated protein that we named p18^Hamlet, which becomes stabilized and accumulates in response to certain genotoxic stresses such as UV or cisplatin treatment. Overexpression of p18^Hamlet is sufficient to induce apoptosis, whereas its downregulation reduces the apoptotic response to these DNA damage-inducing agents. We show that p18^Hamlet interacts with p53 and stimulates the transcription of several proapoptotic p53 target genes such as PUMA and NOXA. This correlates with enhanced p18 ^Hamlet-induced recruitment of p53 to the promoters. In proliferating cells, low steady-state levels of p18^Hamlet are probably maintained by a p53-dependent negative feedback loop. Therefore, p18^Hamlet is a new cell-fate regulator that links the p38 MAPK and p53 pathways and contributes to the establishment of p53-regulated stress responses.