Kras promotes myeloid differentiation through Wnt/β-catenin signaling
Kras promotes myeloid differentiation through Wnt/β-catenin signaling
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Kras 通过 Wnt/β-catenin 信号传导促进骨髓分化
DOI：
10.1096/fba.2019-00004
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Noriko Yokoyama
中科院分区：
文献类型：
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作者：
Takasugi Nobumasa;Araya Runa;Kamikubo Yuji;Kaneshiro Nanaka;Imaoka Ryosuke;Jin Hao;Kashiyama Taku;Hashimoto Yoshie;Kurosawa Masaru;Uehara Takashi;Nukina Nobuyuki;Sakurai Takashi;五十嵐 陽一;五十嵐 陽一;矢野川 大輝;Noriko Yokoyama
野生型Kras，一种小的GT3，使Ras生长促进信号失活。然而，Kras在髓样细胞分化中的作用仍不清楚。这项研究表明，Kras参与了二甲基亚砜（DMSO）诱导人急性髓性白血病HL-60细胞分化的一种新的调控机制。发现Kras正调节DMSO诱导的分化，Kras的活性在DMSO后增加。抑制Kras可减弱分化的HL-60细胞中的CD 11b表达。GSK 3 β是Wnt信号的重要组成部分，是Kras的下游信号。DMSO处理可显著增强GSK 3 β的磷酸化。此外，抑制GSK 3 β可增强CD 11b表达，并触发β-连环蛋白和Tcf在细胞核中的积聚，以响应DMSO。β-连环蛋白介导的途径抑制剂可阻断CD 11b表达，进一步表明β-连环蛋白参与HL-60细胞的分化。在分化过程中观察到C/EBPα和C/EBP β表达升高，伴有粒细胞集落刺激因子（G-CSF）受体的表达。综上所述，这些发现表明，在DMSO处理HL-60细胞后，Kras与Wnt/β-catenin通路发生串扰，从而调节HL-60细胞的粒细胞分化。这些结果表明Kras在髓样细胞分化过程中起肿瘤抑制剂的作用。
Wild‐type Kras, a small GTPase, inactivates Ras growth‐promoting signaling. However, the role of Kras in differentiation of myeloid cells remains unclear. This study showed the involvement of Kras in a novel regulatory mechanism underlying the dimethyl sulfoxide (DMSO)‐induced differentiation of human acute myeloid leukemia HL‐60 cells. Kras was found to positively regulate DMSO‐induced differentiation, with the activity of Kras increasing upon DMSO. Inhibition of Kras attenuated CD11b expression in differentiated HL‐60 cells. GSK3β, an important component of Wnt signaling, was found to be a downstream signal of Kras. Phosphorylation of GSK3β was markedly enhanced by DMSO treatment. Moreover, inhibition of GSK3β enhanced CD11b expression and triggered the accumulation in the nucleus of β‐catenin and Tcf in response to DMSO. Inhibitors of β‐catenin‐mediated pathways blocked CD11b expression, further indicating that β‐catenin is involved in the differentiation of HL‐60 cells. Elevated expression of C/EBPα and C/EBPɛ accompanied by the expression of granulocyte colony‐stimulating factor (G‐CSF) receptor was observed during differentiation. Taken together, these findings suggest that Kras engages in cross talk with the Wnt/β‐catenin pathway upon DMSO treatment of HL‐60 cells, thereby regulating the granulocytic differentiation of HL‐60 cells. These results indicate that Kras acts as a tumor suppressor during the differentiation of myeloid cells.