Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub M P, Durand B, Lanotte M, Berger R, Chambon P
Laboratoire de Génétique Moléculaire des Eucaryotes, CNRS, INSERM, Faculté de Médecine 11, Strasbourg, France.
EMBO J. 1992 Feb;11(2):629-42. doi: 10.1002/j.1460-2075.1992.tb05095.x.
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 alpha (RAR-alpha) 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-alpha 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-alpha. Most notably, MylRAR represses 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-alpha originating from the normal allele. Taken together, these results suggest that MylRAR may interfere in a dominant manner with both Myl and RAR functions.
急性早幼粒细胞白血病（APL）是由染色体t(15;17)易位引起的，该易位涉及一个新的人类基因Myl（也称为PML）和维甲酸（RA）受体α（RAR-α）基因。我们在此报告了在两类APL患者中发现的Myl以及相互的MylRAR（PMLRAR）和RARMyl（RARPML）融合转录本的特征。Myl与一个新的蛋白质家族相似，其中一些成员在转化蛋白RFP-ret和T18中与原癌基因融合。Myl的斑点状核定位及其与RO/SSA核糖核蛋白颗粒52 kDa成分的序列同源性表明，Myl可能存在于核糖核蛋白复合物中。与Myl和RAR-α不同，无论有无RA，它们的定位基本都在细胞核中，而在无RA时主要位于细胞质中的MylRAR在有RA时似乎会转移到细胞核中。Myl和MylRAR在体外可以结合，这种结合由Myl序列中的卷曲螺旋介导。在体内，这种结合导致Myl和MylRAR共定位，这与单独的MylRAR的共定位相同。对几个RA靶基因启动子转录激活的研究表明，与RAR-α相比，MylRARs的转录激活特性发生了改变。最显著的是，在无RA时，MylRAR明显抑制一些RA靶启动子的活性。对患者样本的蛋白质印迹分析表明，MylRAR的表达水平比源自正常等位基因的野生型RAR-α高得多。综上所述，这些结果表明MylRAR可能以显性方式干扰Myl和RAR的功能。
