The ubiquitin-proteasome pathway plays essential roles in ATRA-induced leukemia cells G0/G1 phase arrest and transition into granulocytic differentiation
The ubiquitin-proteasome pathway plays essential roles in ATRA-induced leukemia cells G0/G1 phase arrest and transition into granulocytic differentiation
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DOI：
10.4161/cbt.10.11.13556
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发表时间：
2010-12-01
影响因子：
3.6
通讯作者：
He, Qiaojun
中科院分区：
文献类型：
--
作者：
Fang, Yanfen;Zhou, Xinglu;He, Qiaojun
全反式维甲酸(ATRA)已在临床上成功地用于急性早幼粒细胞白血病(APL)的分化治疗。全反式维甲酸诱导的白血病细胞分化伴随着G0/G1期的停滞，然而全反式维甲酸是如何将细胞周期停滞与分化联系在一起的还很大程度上还不清楚。在此，我们观察到ATRA处理人急性髓系白血病细胞株NB4和HL-60后，泛素-蛋白酶体途径(UPP)被激活，表现为泛素化蛋白的积累，泛素mRNA的上调和20S蛋白酶体活性的增加。有趣的是，我们发现，蛋白酶体活性的完全抑制抑制了ATRA诱导的两种细胞系的增殖/分化(P/D)转变。此外，我们还证明，在这两种细胞系中，导致这种现象的确切蛋白质是不同的。细胞周期蛋白依赖性激酶2(CDK2)和细胞周期蛋白E被UPP降解；在ATRA处理的NB4和HL-60细胞中，它们分别在完全抑制蛋白酶体后显著积聚。提示UPP在ATRA诱导白血病细胞G0/G1期停滞和分化过程中可能起着不可或缺的作用。被UPP降解以促进由维甲酸启动的髓系成熟程序的确切蛋白质可能取决于细胞类型。
All-trans retinoic acid (ATRA) has been successfully used in differentiation therapy for acute promyelocytic leukemia (APL) in the clinic. ATRA-induced differentiation of leukemia cells is accompanied by a G0/G1 arrest, yet how ATRA couples cell cycle arrest to differentiation remains largely unknown. Here we observed that the ubiquitin-proteasome pathway (UPP) was activated upon ATRA treatment in the human acute myeloid leukemia cell lines, NB4 and HL-60, as represented by the accumulation of ubiquitinated proteins, the up-regulation of ubiquitin mRNA and increased 20S proteasome activity. Interestingly, we found that complete inhibition of proteasome activity suppressed ATRA-induced proliferation/differentiation (P/D) transition in both cell lines. Furthermore, we demonstrate that the exact protein contributing to this phenomenon is different in these two cell lines. Cyclin-dependent kinase 2 (CDK2) and Cyclin E were degraded by the UPP; they accumulated significantly after complete inhibition of the proteasome in ATRA-treated NB4 and HL-60 cells, respectively. These findings suggested that the UPP might be indispensable in the ATRA-induced G0/G1 arrest and differentiation of leukemia cells. The exact protein degraded by the UPP to promote the myeloid maturation program set in motion by the retinoid may be cell type dependent.