Formation of PML/RARα high molecular weight nuclear complexes through the PML coiled-coil region is essential for the PML/RARα-mediated retinoic acid response

Francesco Grignani, Vania Gelmetti, Mirco Fanelli, Daniela Rogaia, Silvia De Matteis, Fabiana F. Ferrara, Desirèe Bonci, Fausto Grignani, Clara Nervi, Pier Giuseppe Pelicci

Research output: Contribution to journalArticle

Abstract

Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic Leukaemia (APL) patients by triggering terminal differentiation of neoplastic cells. RA-sensitivity in APL is mediated by its oncogenic protein, which results from the recombination of the PML and the RA receptor α (RARα) genes (PML/RARα fusion protein). Ectopic expression of PML/RARα into haemopoietic cell lines results in increased response to RA-induced differentiation. By structure-function analysis of PML/RARα-mediated RA-differentiation, we demonstrated that fusion of PML and RARα sequences and integrity of the PML dimerization domain and of the RARα DNA binding region are required for the effect of PML/RARα on RA-differentiation. Indeed, direct fusion of the PML dimerization domain to the N- or C-terminal extremities of RARα retained full biological activity. All the biologically active PML/RARα mutants formed high molecular weight complexes in vivo. Functional analysis of mutations within the PML dimerization domain revealed that the capacity to form PML/RARα homodimers, but not PML/RARα-PML heterodimers, correlated with the RA-response. These results suggest that targeting of RARα sequences by the PML dimerization domain and formation of nuclear PML/RARα homodimeric complexes are crucial for the ability of PML/RARα to mediate RA-response.

Original languageEnglish
Pages (from-to)6313-6321
Number of pages9
JournalOncogene
Volume18
Issue number46
Publication statusPublished - Nov 4 1999

Keywords

  • Leukaemia
  • PML/RARα
  • Protein complexes
  • Retinoic acid

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Grignani, F., Gelmetti, V., Fanelli, M., Rogaia, D., De Matteis, S., Ferrara, F. F., Bonci, D., Grignani, F., Nervi, C., & Pelicci, P. G. (1999). Formation of PML/RARα high molecular weight nuclear complexes through the PML coiled-coil region is essential for the PML/RARα-mediated retinoic acid response. Oncogene, 18(46), 6313-6321.