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.
In: Oncogene, Jg. 18 (1999-11-04), Heft 46, S. 6313-6321
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Zugriff:
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. [ABSTRACT FROM AUTHOR]
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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.
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Autor/in / Beteiligte Person: | Grignani, Francesco ; Gelmetti, Vania ; Fanelli, Mirco ; Rogaia, Daniela ; De Matteis, Silvia ; Ferrara, Fabiana F ; Bonci, Desirèe ; Grignani, Fausto ; Nervi, Clara ; Pelicci, Pier Giuseppe |
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Zeitschrift: | Oncogene, Jg. 18 (1999-11-04), Heft 46, S. 6313-6321 |
Veröffentlichung: | 1999 |
Medientyp: | academicJournal |
ISSN: | 0950-9232 (print) |
DOI: | 10.1038/sj.onc.1203029 |
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