Retinoic Acid Receptor α Fusion to PML Affects Its Transcriptional and Chromatin-Remodeling Properties

Simona Segalla, Laura Rinaldi, Charlotte Kilstrup-Nielsen, Gianfranco Badaracco, Saverio Minucci, Pier Giuseppe Pelicci, Nicoletta Landsberger

Research output: Contribution to journalArticle

Abstract

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 RARα 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.

Original languageEnglish
Pages (from-to)8795-8808
Number of pages14
JournalMolecular and Cellular Biology
Volume23
Issue number23
DOIs
Publication statusPublished - Dec 2003

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ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

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