p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells
p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells
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DOI：
10.1038/leu.2012.50
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发表时间：
2012-08-01
期刊：
影响因子：
11.4
通讯作者：
Garattini, E.
中科院分区：
文献类型：
--
作者：
Gianni, M.;Peviani, M.;Garattini, E.
全反式维甲酸（ATRA）是临床上唯一有用的鉴别剂，用于治疗急性早幼粒细胞白血病（APL）。在其他类型的急性髓性白血病（AML）中使用ATRA需要确定旨在增加其治疗活性的新策略。在这里，我们提供的证据表明，药物抑制有丝分裂原激活的蛋白激酶p38 α，或沉默相应的基因，可使APL和AML细胞系以及AML原代培养细胞对ATRA和合成类维生素a的抗增殖和细胞分化活性增敏。P38 α抑制核维甲酸受体RAR α的配体依赖性转激活，以及在大多数APL病例中表达的衍生嵌合蛋白PML-RAR α。抑制作用是p38 α与配体无关的结合的结果，通过阻断蛋白酶体对RAR α和PML-RAR α的组成降解，导致RAR α和PML-RAR α的稳定。抑制作用需要具有催化活性的p38 α和与RAR α和PML-RAR α的直接物理相互作用。RAR α e区的Ser-369对于p38 α的结合以及随后对受体活性的功能影响至关重要。
All-trans retinoic acid (ATRA) is the only clinically useful differentiating agent, being used in the treatment of acute promyelocytic leukemia (APL). The use of ATRA in other types of acute myelogenous leukemia (AML) calls for the identification of novel strategies aimed at increasing its therapeutic activity. Here, we provide evidence that pharmacological inhibition of the mitogen-activated protein kinase, p38 alpha, or silencing of the corresponding gene sensitizes APL and AML cell lines, as well as primary cultures of AML blasts to the anti-proliferative and cyto-differentiating activity of ATRA and synthetic retinoids. P38 alpha inhibits ligand-dependent transactivation of the nuclear retinoic acid receptor, RAR alpha, and the derived chimeric protein expressed in the majority of APL cases, PML-RAR alpha. Inhibition is the consequence of ligand-independent binding of p38 alpha, which results in stabilization of RAR alpha and PML-RAR alpha via blockade of their constitutive degradation by the proteasome. The inhibitory effect requires a catalytically active p38 alpha and direct physical interaction with RAR alpha and PML-RAR alpha. Ser-369 in the E-region of RAR alpha is essential for the binding of p38 alpha and the ensuing functional effects on the activity of the receptor.