Yoshida H, Kitamura K, Tanaka K, Omura S, Miyazaki T, Hachiya T, Ohno R, Naoe T
Department of Medicine, Nagoya University Branch Hospital, Japan.
Cancer Res. 1996 Jul 1;56(13):2945-8.
Acute promyelocytic leukemia (APL) is associated with a chromosomal translocation t(15;17) and successfully differentiated by all-trans-retinoic acid (ATRA) in vivo as well as in vitro. The PML-retinoic acid receptor alpha (RARA) oncoprotein, which is generated by the translocation, blocks the differentiation, and ATRA is thought to modulate the dominant negative function of PML-RARA. However, the molecular effect of ATRA on PML-RARA is unknown. In this study, we showed by means of immunoblotting that the expression of PML-RARA decreased within 12 h in APL cells treated with ATRA at concentrations greater than 0.1 microM. The decrease of PML-RARA was associated with restoration of the normal subcellular PML localization. PML-RARA transcripts were not down-regulated by ATRA. However, lactacystin, a specific inhibitor of the proteasome, almost completely inhibited the decrease of PML-RARA. These data indicate that the PML-RARA degradation is accelerated by pharmacological concentrations of ATRA, suggesting that ATRA allows APL cells to differentiate by relieving the differentiation block.
急性早幼粒细胞白血病（APL）与染色体易位t(15;17)相关，并且在体内和体外均可被全反式维甲酸（ATRA）成功诱导分化。由该易位产生的早幼粒细胞白血病-维甲酸受体α（PML-RARA）癌蛋白会阻断细胞分化，而ATRA被认为可调节PML-RARA的显性负性作用。然而，ATRA对PML-RARA的分子作用尚不清楚。在本研究中，我们通过免疫印迹法表明，在浓度大于0.1微摩尔的ATRA处理的APL细胞中，PML-RARA的表达在12小时内下降。PML-RARA的下降与正常亚细胞PML定位的恢复相关。ATRA并未下调PML-RARA转录本。然而，蛋白酶体的特异性抑制剂乳胞素几乎完全抑制了PML-RARA的下降。这些数据表明，药理学浓度的ATRA加速了PML-RARA的降解，提示ATRA通过解除分化阻滞使APL细胞得以分化。
