Weng Xiang-Qin, Sheng Yan, Ge Dong-Zheng, Wu Jing, Shi Lei, Cai Xun
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Hematology, Peace Hospital of Changzhi Medical College, Changzhi 046000, China.
Leuk Res. 2016 Jun;45:68-74. doi: 10.1016/j.leukres.2016.03.008. Epub 2016 Mar 31.
MEK/ERK signal pathway was required for the differentiation of granulocytes, megakaryocytes and erythrocytes. Recently, MEK/ERK cascade was reported to be involved in all-trans retinoic acid (ATRA) induced differentiation in acute promyelocytic leukemia (APL) cells. However, the upstream and downstream molecules of MEK/ERK signal pathway in this cell model remains to be elucidated. In this work, we showed that RAF-1 was activated and the blockade of RAF-1 activation attenuated MEK/ERK activation as well as ATRA-induced differentiation. ATRA-enhanced protein levels of C/EBPβ, C/EBPε and PU.1, which were required for differentiation in APL cells, were suppressed by the specific inhibitor of MEK. However, MEK inhibition had no effect on the degradation of PML-RARα fusion protein or the restoration of PML nuclear bodies by ATRA treatment. Taken together, our study suggested that RAF-1/MEK/ERK cascade was involved in ATRA-induced differentiation in APL cells through enhancing the protein level of C/EBPβ, C/EBPε and PU.1.
MEK/ERK信号通路对于粒细胞、巨核细胞和红细胞的分化是必需的。最近，有报道称MEK/ERK级联参与全反式维甲酸（ATRA）诱导的急性早幼粒细胞白血病（APL）细胞分化。然而，在该细胞模型中，MEK/ERK信号通路的上游和下游分子仍有待阐明。在这项研究中，我们发现RAF-1被激活，阻断RAF-1激活会减弱MEK/ERK激活以及ATRA诱导的分化。MEK的特异性抑制剂可抑制ATRA增强的C/EBPβ、C/EBPε和PU.1蛋白水平，而这些蛋白是APL细胞分化所必需的。然而，MEK抑制对ATRA处理导致的PML-RARα融合蛋白降解或PML核体恢复没有影响。综上所述，我们的研究表明，RAF-1/MEK/ERK级联通过提高C/EBPβ、C/EBPε和PU.1的蛋白水平参与ATRA诱导的APL细胞分化。
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