Structure, localization and transcriptional properties of two classes of retinoic acid receptor α fusion proteins in acute promyelocytic leukemia (APL): Structural similarities with a new family of oncoproteins

Philippe Kastner, Aymee Perez, Yves Lutz, Cécile Rochette-Egly, Marie Pierre Gaub, Béatrice Durand, Michel Lanotte, Roland Berger, Pierre Chambon

Research output: Contribution to journalArticle

395 Citations (Scopus)

Abstract

Acute promyelocytic leukemia (APL) is due to a chromosomal t(15;17) translocation which involves a novel human gene, Myl, (also named PML) and the retinoic acid (RA) receptor α (RAR-α) gene. We report here the characterization of Myl and of the reciprocal MylRAR (PMLRAR) and RARMyl (RARPML) fusion transcripts which are found in two classes of APL patients. Myl displays similarities with a new family of proteins of which some members are fused to protooncogenes in the transforming proteins RFP-ret and T18. The speckled nuclear localization of Myl, as well as its sequence homology with the 52 kDa component of the RO/SSA ribonucleoprotein particle, suggest that Myl may be present in a ribonucleoprotein complex. In contrast to both Myl and RAR-α whose localization is essentially nuclear in the presence or absence of RA, MylRAR which is largely cytoplasmic in the absence of RA appears to be translocated to the nucleus in the presence of RA. Myl and MylRAR can associate in vitro and this association is mediated by a coiled coil in the Myl sequence. In vivo this association results in a colocalization of Myl and MylRAR which is identical to that of MylRAR alone. Studies of activation of transcription from the promoters of several RA target genes indicate that MylRARs have altered transcription activation properties when compared with RAR-α. Most notably, MylRAR repressses markedly the activity of some RA target promoters in the absence of RA. Western blot analyses of patient samples show that MylRAR is expressed to a much higher level than wild type RAR-α originating from the normal allele. Taken together, these results suggest that MylRAR may interfere in a dominant manner with both Myl and RAR functions.

Original languageEnglish
Pages (from-to)629-642
Number of pages14
JournalEMBO Journal
Volume11
Issue number2
StatePublished - Dec 1 1992
Externally publishedYes

Fingerprint

Acute Promyelocytic Leukemia
Retinoic Acid Receptors
Oncogene Proteins
Tretinoin
Fusion reactions
Proteins
Ribonucleoproteins
Genes
Transcription
Transcriptional Activation
Chemical activation
Association reactions
Sequence Homology
Western Blotting
Alleles

Keywords

  • APL
  • Coiled coil
  • Myl (PML)
  • MylRAR (PMLRAR) fusion
  • RAR-α
  • RARMyl (RARPML) fusion

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Structure, localization and transcriptional properties of two classes of retinoic acid receptor α fusion proteins in acute promyelocytic leukemia (APL) : Structural similarities with a new family of oncoproteins. / Kastner, Philippe; Perez, Aymee; Lutz, Yves; Rochette-Egly, Cécile; Gaub, Marie Pierre; Durand, Béatrice; Lanotte, Michel; Berger, Roland; Chambon, Pierre.

In: EMBO Journal, Vol. 11, No. 2, 01.12.1992, p. 629-642.

Research output: Contribution to journalArticle

Kastner, Philippe ; Perez, Aymee ; Lutz, Yves ; Rochette-Egly, Cécile ; Gaub, Marie Pierre ; Durand, Béatrice ; Lanotte, Michel ; Berger, Roland ; Chambon, Pierre. / Structure, localization and transcriptional properties of two classes of retinoic acid receptor α fusion proteins in acute promyelocytic leukemia (APL) : Structural similarities with a new family of oncoproteins. In: EMBO Journal. 1992 ; Vol. 11, No. 2. pp. 629-642.
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abstract = "Acute promyelocytic leukemia (APL) is due to a chromosomal t(15;17) translocation which involves a novel human gene, Myl, (also named PML) and the retinoic acid (RA) receptor α (RAR-α) gene. We report here the characterization of Myl and of the reciprocal MylRAR (PMLRAR) and RARMyl (RARPML) fusion transcripts which are found in two classes of APL patients. Myl displays similarities with a new family of proteins of which some members are fused to protooncogenes in the transforming proteins RFP-ret and T18. The speckled nuclear localization of Myl, as well as its sequence homology with the 52 kDa component of the RO/SSA ribonucleoprotein particle, suggest that Myl may be present in a ribonucleoprotein complex. In contrast to both Myl and RAR-α whose localization is essentially nuclear in the presence or absence of RA, MylRAR which is largely cytoplasmic in the absence of RA appears to be translocated to the nucleus in the presence of RA. Myl and MylRAR can associate in vitro and this association is mediated by a coiled coil in the Myl sequence. In vivo this association results in a colocalization of Myl and MylRAR which is identical to that of MylRAR alone. Studies of activation of transcription from the promoters of several RA target genes indicate that MylRARs have altered transcription activation properties when compared with RAR-α. Most notably, MylRAR repressses markedly the activity of some RA target promoters in the absence of RA. Western blot analyses of patient samples show that MylRAR is expressed to a much higher level than wild type RAR-α originating from the normal allele. Taken together, these results suggest that MylRAR may interfere in a dominant manner with both Myl and RAR functions.",
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AU - Lutz, Yves

AU - Rochette-Egly, Cécile

AU - Gaub, Marie Pierre

AU - Durand, Béatrice

AU - Lanotte, Michel

AU - Berger, Roland

AU - Chambon, Pierre

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AB - Acute promyelocytic leukemia (APL) is due to a chromosomal t(15;17) translocation which involves a novel human gene, Myl, (also named PML) and the retinoic acid (RA) receptor α (RAR-α) gene. We report here the characterization of Myl and of the reciprocal MylRAR (PMLRAR) and RARMyl (RARPML) fusion transcripts which are found in two classes of APL patients. Myl displays similarities with a new family of proteins of which some members are fused to protooncogenes in the transforming proteins RFP-ret and T18. The speckled nuclear localization of Myl, as well as its sequence homology with the 52 kDa component of the RO/SSA ribonucleoprotein particle, suggest that Myl may be present in a ribonucleoprotein complex. In contrast to both Myl and RAR-α whose localization is essentially nuclear in the presence or absence of RA, MylRAR which is largely cytoplasmic in the absence of RA appears to be translocated to the nucleus in the presence of RA. Myl and MylRAR can associate in vitro and this association is mediated by a coiled coil in the Myl sequence. In vivo this association results in a colocalization of Myl and MylRAR which is identical to that of MylRAR alone. Studies of activation of transcription from the promoters of several RA target genes indicate that MylRARs have altered transcription activation properties when compared with RAR-α. Most notably, MylRAR repressses markedly the activity of some RA target promoters in the absence of RA. Western blot analyses of patient samples show that MylRAR is expressed to a much higher level than wild type RAR-α originating from the normal allele. Taken together, these results suggest that MylRAR may interfere in a dominant manner with both Myl and RAR functions.

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