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  • The EMBO Journal (2002) 21, 3358 - 3369
  • doi:10.1093/emboj/cdf341

Deconstructing PML-induced premature senescence

Oliver Bischof1, Olivier Kirsh1, Mark Pearson2, Koji Itahana3, Pier Giuseppe Pelicci2 and Anne Dejean1

  1. Unité de Recombinaison et Expression Génétique, INSERM U 163, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France
  2. European Institute of Oncology, Department of Experimental Oncology, 20141 Milan, Italy
  3. Department of Cell and Molecular Biology, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA

Correspondence to:

Anne Dejean, E-mail: adejean@pasteur.fr

Received 11 February 2002; Accepted 7 May 2002; Revised 3 May 2002

In this study, we investigated the subcellular and molecular mechanisms underlying promyelocytic leu kemia (PML)-induced premature senescence. We demonstrate that intact PML nuclear bodies are not required for the induction of senescence. We have determined further that of seven known PML isoforms, only PML IV is capable of causing premature senescence, providing the first evidence for functional differences among these isoforms. Of interest is the fact that in contrast to PML+/+ fibroblasts, PML-/- cells are resistant to PML IV-induced senescence. This suggests that although PML IV is necessary for this process to occur, it is not sufficient and requires other components for activity. Finally, we provide evidence that PML IV-induced senescence involves stabilization and activation of p53 through phosphorylation at Ser46 and acetylation at Lys382, and that it occurs independently of telomerase and differs from that elicited by oncogenic Ras. Taken together, our data assign a specific pro-senescent activity to an individual PML isoform that involves p53 activation and is independent from PML nuclear bodies.

  • Keywords:

    • p53,
    • PML,
    • PML nuclear bodies,
    • senescence,
    • telomerase