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

Marta Fagioli, Myriam Alcalay, Lucia Tomassoni, Pier Francesco Ferrucci, Amedea Mencarelli, Daniela Riganelli, Francesco Grignani, Tullio Pozzan, Ildo Nicoletti, Fausto Grignani, Pier Giuseppe Pelicci

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2905-2913
Number of pages9
JournalOncogene
Volume16
Issue number22
Publication statusPublished - Jun 4 1998

Fingerprint

Cell Survival
Growth
Proteins
Acute Promyelocytic Leukemia
Histidine
Protein Isoforms
Cytoplasm
Cell Death
Phenotype
Cell Line

Keywords

  • Apoptotic cell death
  • B-boxes
  • Coiled-coil
  • PML
  • Ring

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Cooperation between the RING + B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival. / Fagioli, Marta; Alcalay, Myriam; Tomassoni, Lucia; Ferrucci, Pier Francesco; Mencarelli, Amedea; Riganelli, Daniela; Grignani, Francesco; Pozzan, Tullio; Nicoletti, Ildo; Grignani, Fausto; Pelicci, Pier Giuseppe.

In: Oncogene, Vol. 16, No. 22, 04.06.1998, p. 2905-2913.

Research output: Contribution to journalArticle

Fagioli, M, Alcalay, M, Tomassoni, L, Ferrucci, PF, Mencarelli, A, Riganelli, D, Grignani, F, Pozzan, T, Nicoletti, I, Grignani, F & Pelicci, PG 1998, 'Cooperation between the RING + B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival', Oncogene, vol. 16, no. 22, pp. 2905-2913.
Fagioli, Marta ; Alcalay, Myriam ; Tomassoni, Lucia ; Ferrucci, Pier Francesco ; Mencarelli, Amedea ; Riganelli, Daniela ; Grignani, Francesco ; Pozzan, Tullio ; Nicoletti, Ildo ; Grignani, Fausto ; Pelicci, Pier Giuseppe. / Cooperation between the RING + B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival. In: Oncogene. 1998 ; Vol. 16, No. 22. pp. 2905-2913.
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