BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP
BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP
复制标题
DOI：
10.1038/leu.2013.370
复制
发表时间：
2014-06-01
期刊：
影响因子：
11.4
通讯作者：
Pandolfi, P. P.
中科院分区：
文献类型：
--
作者：
Morotti, A.;Panuzzo, C.;Pandolfi, P. P.
慢性髓性白血病（CML）是一种以嵌合蛋白p210 BCR-ABL的t（9; 22）易位编码为特征的骨髓增生性疾病。肿瘤抑制磷酸酶和紧张素同源物（PTEN）最近被证明在CML的发病机制中起关键作用。核定位和适当的核-胞质穿梭是PTEN抑制肿瘤功能的关键。在这项研究中，我们发现BCR-ABL增强了hausp诱导的PTEN的去泛素化，反过来有利于其核排斥。我们进一步证明BCR-ABL与酪氨酸残基上的HAUSP发生物理相互作用并使其磷酸化以触发其活性。重要的是，我们还发现BCR-ABL诱导的PTEN脱位不会发生在白血病干细胞室中，这是由于PML的高水平，PML是HAUSP对PTEN活性的有效抑制剂。因此，我们确定了一种新的原致癌机制，其中BCR-ABL拮抗PTEN肿瘤抑制因子的核功能，对根除CML微小残留病具有重要的治疗意义。
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the t(9; 22) translocation coding for the chimeric protein p210 BCR-ABL. The tumor suppressor phosphatase and tensin homolog (PTEN) has recently been shown to have a critical role in the pathogenesis of CML. Nuclear localization and proper nuclear-cytoplasmic shuttling are crucial for PTEN's tumor suppressive function. In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity. Importantly, we also find that PTEN delocalization induced by BCR-ABL does not occur in the leukemic stem cell compartment due to high levels of PML, a potent inhibitor of HAUSP activity toward PTEN. We therefore identify a new proto-oncogenic mechanism whereby BCR-ABL antagonizes the nuclear function of the PTEN tumor suppressor, with important therapeutic implications for the eradication of CML minimal residual disease.