Bischof Oliver, Kirsh Olivier, Pearson Mark, Itahana Koji, Pelicci Pier Giuseppe, Dejean Anne
Unité de Recombinaison et Expression Génétique, INSERM U 163, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
EMBO J. 2002 Jul 1;21(13):3358-69. doi: 10.1093/emboj/cdf341.
In this study, we investigated the subcellular and molecular mechanisms underlying promyelocytic leukemia (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.
在本研究中，我们探究了早幼粒细胞白血病（PML）诱导细胞早衰的亚细胞和分子机制。我们证明，衰老诱导并不需要完整的PML核体。我们进一步确定，在七种已知的PML亚型中，只有PML IV能够导致细胞早衰，这为这些亚型之间的功能差异提供了首个证据。有趣的是，与PML(+/+)成纤维细胞相反，PML(-/-)细胞对PML IV诱导的衰老具有抗性。这表明，虽然PML IV是该过程发生所必需的，但并不充分，还需要其他成分来发挥作用。最后，我们提供证据表明，PML IV诱导的衰老涉及通过Ser46磷酸化和Lys382乙酰化来稳定和激活p53，并且它独立于端粒酶发生，且不同于致癌性Ras引发的衰老。综上所述，我们的数据赋予了单个PML亚型一种特定的促衰老活性，该活性涉及p53激活且独立于PML核体。
