Cooperation between the RING+B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival (original) (raw)

Oncogene volume 16, pages 2905–2913 (1998)Cite this article

Abstract

PML/RARα is the abnormal protein product of the Acute Promyelocytic Leukemia-specific 15;17 translocation. Both the PML and RARα components are required for the PML/RARα biological activities, namely its capacity to block differentiation and to increase survival of haematopoietic precursors. The physiological role of PML and its contribution to the function of the fusion protein are unknown. PML localizes to the cytoplasm and within specific nuclear bodies (NBs). In vitro, overexpression of PML correlates with suppression of cell transformation. The PML aminoterminal portion retained within the PML/RARα protein contains the RING finger, two newly defined cystein/histidine-rich motifs called B-boxes (B1 and B2) and a coiled-coil region. We report here that PML has a growth suppressive activity in all the cell lines tested, regardless of their transformed phenotype, and that the cellular basis for the PML growth suppression is induction of apoptotic cell death. Analysis of various nuclear and cytoplasmic PML isoforms showed that the PML growth suppressive activity correlates with its nuclear localization. Analysis of the localization and growth suppressive activity demonstrated that: (i) the Ring+B1-B2 and coiled-coil regions are both indispensable and sufficient to target PML to the NBs; (ii) individual deletions of the various PML domains have no effect on its growth suppressor activity; (iii) the Ring+B1-B2 region exerts a partial growth suppressor activity but its fusion with the coiled-coil region is sufficient to recapitulate the suppressive function of wild type PML. These results indicate that PML is involved in cell survival regulation and that the PML component of the fusion protein (Ring+B1-B2 and coiled-coil regions) retains intact biological activity, thereby suggesting that the effects of PML/RARα on survival derive from the activation of the incorporated PML sequence.

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Authors and Affiliations

  1. Istituto di Medicina Intema e Scienze Oncologiche, Università degli Studi di Perugia, Policlinico Monteluce, Perugia, 06100, Italy
    Marta Fagioli, Amedea Mencarelli, Daniela Riganelli, Francesco Grignani, Ildo Nicoletti, Fausto Grignani & Pier Giuseppe Pelicci
  2. Department of Experimental Oncology, European Institute of Oncology, Milan, 20141, Italy
    Myriam Alcalay, Lucia Tomassoni, Pier Francesco Ferrucci & Pier Giuseppe Pelicci
  3. Department of Biomedical Sciences and CNR Center for the Study of Mitochondrial Physiology, University of Padova, Via Trieste 75, Padova, 35121, Italy
    Tullio Pozzan

Authors

  1. Marta Fagioli
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  2. Myriam Alcalay
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  3. Lucia Tomassoni
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  4. Pier Francesco Ferrucci
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  5. Amedea Mencarelli
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  6. Daniela Riganelli
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  7. Francesco Grignani
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  8. Tullio Pozzan
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  9. Ildo Nicoletti
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  10. Fausto Grignani
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  11. Pier Giuseppe Pelicci
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Fagioli, M., Alcalay, M., Tomassoni, L. et al. Cooperation between the RING+B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival.Oncogene 16, 2905–2913 (1998). https://doi.org/10.1038/sj.onc.1201811

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