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Molecular and Cellular Biology, December 2003, p. 8795-8808, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8795-8808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Retinoic Acid Receptor {alpha} Fusion to PML Affects Its Transcriptional and Chromatin-Remodeling Properties

Simona Segalla,1 Laura Rinaldi,1 Charlotte Kilstrup-Nielsen,1 Gianfranco Badaracco,1 Saverio Minucci,2 Pier Giuseppe Pelicci,2 and Nicoletta Landsberger1*

Dipartimento di Biologia Strutturale e Funzionale, Università dell'Insubria, 21052 Busto Arsizio (VA),1 Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy2

Received 16 July 2003/ Accepted 20 August 2003

PML-RAR is an oncogenic transcription factor forming in acute promyelocytic leukemias (APL) because of a chromosomal translocation. Without its ligand, retinoic acid (RA), PML-RAR functions as a constitutive transcriptional repressor, abnormally associating with the corepressor-histone deacetylase complex and blocking hematopoietic differentiation. In the presence of pharmacological concentrations of RA, PML-RAR activates transcription and stimulates differentiation. Even though it has been suggested that chromatin alteration is important for APL onset, the PML-RAR effect on chromatin of target promoters has not been investigated. Taking advantage of the Xenopus oocyte system, we compared the wild-type transcription factor RAR{alpha} with PML-RAR as both transcriptional regulators and chromatin structure modifiers. Without RA, we found that PML-RAR is a more potent transcriptional repressor that does not require the cofactor RXR and produces a closed chromatin configuration. Surprisingly, repression by PML-RAR occurs through a further pathway that is independent of nucleosome deposition and histone deacetylation. In the presence of RA, PML-RAR is a less efficient transcriptional activator that is unable to modify the DNA nucleoprotein structure. We propose that PML-RAR, aside from its ability to recruit aberrant quantities of histone deacetylase complexes, has acquired additional repressive mechanisms and lost important activating functions; the comprehension of these mechanisms might reveal novel targets for antileukemic intervention.

* Corresponding author. Mailing address: Dipartimento di Biologia Strutturale e Funzionale, Università dell'Insubria, Via Alberto da Giussano 12, 21052 Busto Arsizio (VA), Italy. Phone: 390331339406. Fax: 390331339459. E-mail: landsben{at}uninsubria.it.

Molecular and Cellular Biology, December 2003, p. 8795-8808, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8795-8808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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