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  • The EMBO Journal (2007) 26, 2115 - 2126
  • doi:10.1038/sj.emboj.7601657

Published online: 22 March 2007

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

Ana Cuadrado1, Vanesa Lafarga1, Peter CF Cheung2,a, Ignacio Dolado1, Susana Llanos1, Philip Cohen2 and Angel R Nebreda1

  1. CNIO (Spanish National Cancer Center), Madrid, Spain
  2. MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK

Correspondence to:

Ana CuadradoAngel R Nebreda, Molecular Oncology Programme, CNIO (Spanish National Cancer Center), Melchor Fernández Almagro 3, Madrid -28029 Spain. Tel.: +34 91 2246900; Fax: +34 91 7328033; E-mail: anebreda@cnio.es or acuadrado@cnio.es

aPresent address: Nanyang Technological University, Singapore

Received 15 August 2006; Accepted 26 February 2007

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 p18Hamlet, which becomes stabilized and accumulates in response to certain genotoxic stresses such as UV or cisplatin treatment. Overexpression of p18Hamlet is sufficient to induce apoptosis, whereas its downregulation reduces the apoptotic response to these DNA damage-inducing agents. We show that p18Hamlet interacts with p53 and stimulates the transcription of several proapoptotic p53 target genes such as PUMA and NOXA. This correlates with enhanced p18Hamlet-induced recruitment of p53 to the promoters. In proliferating cells, low steady-state levels of p18Hamlet are probably maintained by a p53-dependent negative feedback loop. Therefore, p18Hamlet is a new cell-fate regulator that links the p38 MAPK and p53 pathways and contributes to the establishment of p53-regulated stress responses.

  • Keywords:

    • apoptosis,
    • p38 MAP kinase,
    • p53,
    • stress response,
    • transcriptional coactivator