Depletion of Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatases 1 and 2 by Bcr-Abl Promotes Chronic Myelogenous Leukemia Cell Proliferation through Continuous Phosphorylation of Akt Isoforms (Retracted Article)
Depletion of Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatases 1 and 2 by Bcr-Abl Promotes Chronic Myelogenous Leukemia Cell Proliferation through Continuous Phosphorylation of Akt Isoforms (Retracted Article)
复制标题
DOI：
10.1074/jbc.m808182200
复制
发表时间：
2009-08-14
影响因子：
4.8
通讯作者：
Ohnishi, Kazunori
中科院分区：
文献类型：
--
作者：
Hirano, Isao;Nakamura, Satoki;Ohnishi, Kazunori
磷脂酰肌醇3-激酶（PI 3 K）/Akt通路的组成性激活通常发生在癌症中，并且是肿瘤发生中的关键事件。慢性粒细胞白血病（CML）的特征是相互染色体易位（9;22），产生Bcr-Abl融合基因。Bcr-Abl嵌合体蛋白激活PI 3 K/Akt通路介导CML的白血病发生然而，Bcr-Abl激活PI 3 K/Akt通路的机制还不完全清楚。在本研究中，我们发现pleckstrin同源结构域富含亮氨酸重复蛋白磷酸酶1和2（PHLPP 1和PHLPP 2）在CML细胞中被耗尽。我们研究了CML细胞系和CML患者Bcr-Abl（+）祖细胞中PHLPPs和Bcr-Abl之间的相互作用。Abl激酶抑制剂和Bcr-Abl的耗竭诱导PHLPP 1和PHLPP 2的表达，其使Akt 1、Akt 2和Akt 3上的Ser-473去磷酸化，导致CML细胞增殖抑制。在CML细胞中，通过短干扰RNA降低PHLPP 1和PHLPP 2表达减弱了Abl激酶介导的增殖抑制。在集落形成单位-粒细胞、红细胞、巨噬细胞、巨核细胞中，集落形成单位-粒细胞、巨噬细胞;和爆发形成单位-红系细胞，Abl激酶抑制剂处理和Bcr-Abl耗竭诱导PHLPP 1和PHLPP 2表达并抑制Bcr-Abl（+）祖细胞的集落形成，而PHLPP 1和PHLPP 2的缺失减弱了Abl激酶抑制剂对Bcr-Abl（+）祖细胞中集落形成活性的抑制。因此，Bcr-Abl抑制PHLPP 1和PHLPP 2的表达，并通过Ser-473上的磷酸化持续激活Akt 1、Akt 2和Akt 3，导致CML细胞增殖。
The constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway commonly occurs in cancers and is a crucial event in tumorigenesis. Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. The PI3K/Akt pathway is activated by Bcr-Abl chimera protein and mediates the leukemogenesis in CML. However, the mechanism by which Bcr-Abl activates the PI3K/Akt pathway is not completely understood. In the present study, we found that pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1 and PHLPP2) were depleted in CML cells. We investigated the interaction between PHLPPs and Bcr-Abl in CML cell lines and Bcr-Abl(+) progenitor cells from CML patients. The Abl kinase inhibitors and depletion of Bcr- Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells. The reduction of PHLPP1 and PHLPP2 expression by short interfering RNA in CML cells weakened the Abl kinase inhibitor-mediated inhibition of proliferation. In colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte; colony-forming unit-granulocyte, macrophage; and burst-forming unit-erythroid, treatment with the Abl kinase inhibitors and depletion of Bcr- Abl induced PHLPP1 and PHLPP2 expression and inhibited colony formation of Bcr-Abl(+) progenitor cells, whereas depletion of PHLPP1 and PHLPP2 weakened the inhibition of colony formation activity by the Abl kinase inhibitors in Bcr-Abl(+) progenitor cells. Thus, Bcr- Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.