CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia
CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia
复制标题
DOI：
10.4161/cc.24313
复制
发表时间：
2013-04-15
期刊：
影响因子：
4.3
通讯作者：
Persson, Jenny L.
中科院分区：
文献类型：
--
作者：
Hedblom, Andreas;Laursen, Kristian B.;Persson, Jenny L.
细胞周期通路和维甲酸信号的改变与白血病的发生有关。然而，目前对细胞周期蛋白依赖性蛋白激酶(CDK)在白血病治疗反应中的作用知之甚少。在本研究中，我们观察到42例急性髓系白血病(AML)患者复发时骨髓中CDK1的表达显著高于初诊时(p=0.04)。AML患者白血病母细胞中CDK1的核表达水平较高，其临床预后较差。我们发现，全反式维甲酸(ATRA)在U-937人白血病细胞中发挥最佳作用需要CDK1功能。CDK1调节ATRA处理后P27(Kip)和AKT的磷酸化水平。此外，我们首次证明，RAR与ATRA协同调节CDK1的蛋白水平及其亚细胞定位。全反式维甲酸对CDK1和RAR亚细胞含量的调节是白血病有效治疗的重要环节。RAR和CDK1在细胞核内形成相互调节的回路，相互影响彼此的功能和蛋白稳定性以及P27(Kip)蛋白水平。此外，Wee1激酶和CDC25A/C磷酸酶的表达也与CDK1的表达及其在ATRA作用下的亚细胞定位相一致。我们的研究揭示了CDK1和RAR与ATRA协同作用影响细胞周期进程和细胞分化的新机制。
Alterations in cell cycle pathways and retinoic acid signaling are implicated in leukemogenesis. However, little is known about the roles of cyclin-dependent kinases (CDKs) in treatment response of leukemia. In this study, we observed that CDK1 expression was significantly higher in bone marrow from 42 patients with acute myeloid leukemia (AML) at recurrence than that at first diagnosis (p = 0.04). AML patients had higher level of nuclear CDK1 in their leukemic blasts tended to have poorer clinical outcome compared with those with lower levels. We showed that CDK1 function is required for all-trans retinoic acid (ATRA) to achieve the optimal effect in U-937 human leukemic cells. CDK1 modulates the levels of P27(kip) and AKT phosphorylation in response to ATRA treatment. Further, we show, for the first time, that RAR in concert with ATRA regulates protein levels of CDK1 and its subcellular localization. The regulation of the subcellular content of CDK1 and RAR by ATRA is an important process for achieving an effective response in treatment of leukemia. RAR and CDK1 form a reciprocal regulatory circuit in the nucleus and influence the function and protein stability of each other and the level of P27(kip) protein. In addition, expression of wee1 kinase and Cdc25A/C phosphatases also coincide with CDK1 expression and its subcellular localization in response to ATRA treatment. Our study reveals a novel mechanism by which CDK1 and RAR coordinate with ATRA to influence cell cycle progression and cellular differentiation.