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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 volume 18, pages 6313–6321 (1999)Cite this article

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.

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Acknowledgements

This work was supported by grants from AIRC, MURST, CNR and EC (BiomedII program).

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Authors and Affiliations

  1. Istituto di Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, 06100, Perugia, Italy

    Francesco Grignani, Vania Gelmetti, Daniela Rogaia, Silvia De Matteis, Desirèe Bonci, Fausto Grignani & Pier Giuseppe Pelicci

  2. Department of Haematology and Oncology, Istituto Superiore di Sanitá, 00161, Rome, Italy

    Francesco Grignani

  3. Dipartimento di Istologia ed Embriologia Umana, Universitá `La Sapienza', 00161, Rome, Italy

    Fabiana F Ferrara & Clara Nervi

  4. Department of Experimental Oncology, European Institute of Oncology, 20141, Milan, Italy

    Vania Gelmetti, Mirco Fanelli & Pier Giuseppe Pelicci

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  1. Francesco Grignani
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Grignani, F., Gelmetti, V., Fanelli, M. et al. 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, 6313–6321 (1999). https://doi.org/10.1038/sj.onc.1203029

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