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p18^Hamlet Mediates Different p53-Dependent Responses to DNA Damage Inducing Agents

Vanesa Lafarga, Ana Cuadrado and Angel R. Nebreda

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Cells organize appropriate responses to environmental cues by activating specific signaling networks. Two proteins that play key roles in coordinating stress responses are the kinase p38α (MAPK14) and the transcription factor p53 (TP53). Depending on the nature and the extent of the stress-induced damage, cells may respond by arresting the cell cycle or by undergoing cell death, and these responses are usually associated with the phosphorylation of particular substrates by p38α as well as the activation of specific target genes by p53. We recently characterized a new p38α substrate, named p18^Hamlet (ZNHIT1), which mediates p53-dependent responses to different genotoxic stresses. Thus, cisplatin or UV light induce stabilization of the p18Hamlet protein, which then enhances the ability of p53 to bind to and activate the promoters of pro-apoptotic genes such as NOXA and PUMA leading to apoptosis induction. In a similar way, we report here that ^Hamlet can also mediate the cell cycle arrest induced in response to γ-irradiation, by participating in the p53-dependent up-regulation of the cell cycle inhibitor p21Cip1 (CDKN1A).

Authors

Vanesa Lafarga

CNIO (Spanish National Cancer Center); Madrid, Spain

Ana Cuadrado

CNIO (Spanish National Cancer Center); Madrid, Spain

Angel R. Nebreda

CNIO (Spanish National Cancer Center); Madrid, Spain

Purchase article for $19

Subscribe to this journal for $129/year