Moog-Lutz C, Peterson E J, Lutz P G, Eliason S, Cavé-Riant F, Singer A, Di Gioia Y, Dmowski S, Kamens J, Cayre Y E, Koretzky G
Unité INSERM 417, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France.
J Biol Chem. 2001 Jun 22;276(25):22375-81. doi: 10.1074/jbc.M011683200. Epub 2001 Apr 11.
The t(15;17) translocation, found in 95% of acute promyelocytic leukemia, encodes a promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) fusion protein. Complete remission of acute promyelocytic leukemia can be obtained by treating patients with all-trans retinoic acid, and PML-RARalpha plays a major role in mediating retinoic acid effects in leukemia cells. A main model proposed for acute promyelocytic leukemia is that PML-RARalpha exerts its oncogenic effects by repressing the expression of retinoic acid-inducible genes critical to myeloid differentiation. By applying subtraction cloning to acute promyelocytic leukemia cells, we identified a retinoic acid-induced gene, PRAM-1 (PML-RARalpha target gene encoding an Adaptor Molecule-1), which encodes a novel adaptor protein sharing structural homologies with the SLAP-130/fyb adaptor. PRAM-1 is expressed and regulated during normal human myelopoiesis. In U937 myeloid precursor cells, PRAM-1 expression is inhibited by expression of PML-RARalpha in the absence of ligand and de novo superinduced by retinoic acid. PRAM-1 associates with other adaptors, SLP-76 and SKAP-55HOM, in myeloid cell lines and with protein tyrosine kinase lyn. By providing the first evidence that PML-RARalpha dysregulates expression of an adaptor protein, our data open new insights into signaling events that are disrupted during transformation by PML-RARalpha and induced by retinoic acid during de novo differentiation of acute promyelocytic leukemia cells.
在95%的急性早幼粒细胞白血病中发现的t(15;17)易位，编码一种早幼粒细胞白血病（PML）-维甲酸受体α（RARα）融合蛋白。通过用全反式维甲酸治疗患者可使急性早幼粒细胞白血病完全缓解，并且PML-RARα在介导白血病细胞中的维甲酸效应方面起主要作用。针对急性早幼粒细胞白血病提出的一个主要模型是，PML-RARα通过抑制对髓系分化至关重要的维甲酸诱导基因的表达来发挥其致癌作用。通过对急性早幼粒细胞白血病细胞应用消减克隆，我们鉴定出一个维甲酸诱导基因，PRAM-1（编码衔接分子-1的PML-RARα靶基因），它编码一种与SLAP-130/fyb衔接蛋白具有结构同源性的新型衔接蛋白。PRAM-1在正常人类髓系造血过程中表达并受调控。在U937髓系前体细胞中，在无配体时PML-RARα的表达抑制PRAM-1的表达，而维甲酸可使其重新诱导表达。在髓系细胞系中，PRAM-1与其他衔接蛋白SLP-76和SKAP-55HOM以及蛋白酪氨酸激酶lyn相关联。通过提供PML-RARα失调调节衔接蛋白表达的首个证据，我们的数据为PML-RARα在转化过程中破坏以及在急性早幼粒细胞白血病细胞重新分化过程中由维甲酸诱导的信号事件开启了新的见解。
