p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells
p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells
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DOI：
10.1093/carcin/bgq211
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发表时间：
2011-01-01
期刊：
影响因子：
4.7
通讯作者：
Della Ragione, Fulvio
中科院分区：
文献类型：
--
作者：
Borriello, Adriana;Caldarelli, Ilaria;Della Ragione, Fulvio
慢性粒细胞白血病（CML）的特征是BCR-ABL酪氨酸激酶的表达，其导致细胞增殖增加和细胞凋亡抑制。在这项研究中，我们发现BCR-ABL阳性CML细胞系经伊马替尼（STI 571）处理后发生G（1）细胞周期阻滞，这与p57（Kip 2）（一种细胞周期蛋白依赖性激酶抑制剂（CKI））的积累有关。有趣的是，p57（Kip 2）的增加先于报道的STI 571依赖性p27（Kip 1）的上调。许多互补的方法允许证明p57（Kip 2）的积累是由于CDKN 1C（p57（Kip 2）编码基因）的转录激活，而既没有观察到p57（Kip 2）半衰期延长也没有观察到其细胞重新定位。我们还鉴定了迄今为止未描述的p57（Kip 2）磷酸化亚型的模式，然而，该模式对STI 571细胞处理没有反应。伊马替尼依赖性p57（Kip 2）上调仅发生在STI 571反应细胞中，而CKI蓄积在伊马替尼耐药克隆中未得到证实。尼洛替尼和达沙替尼（第二代BCR-ABL抑制剂），在与治疗中使用的浓度相当的浓度下，增加CKI，但不影响p271（KiP 1）水平。最后，CML患者的CD 34（+）细胞显示出明显的伊马替尼依赖性p57（Kip 2）上调，而在对照受试者的CD 34（+）细胞中未观察到。总之，我们的研究指出，p57（Kip 2）作为一种新的和早熟的效应BCR-ABL靶向药物。
Chronic myelogenous leukemia (CML) is characterized by the expression of BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show that BCR-ABL-positive CML cell lines treated with imatinib (STI571) undergo G(1) cell cycle arrest associated with the accumulation of p57(Kip2), a cyclin-dependent kinase inhibitor (CKI). Interestingly, p57(Kip2) increase precedes the reported STI571-dependent upregulation of p27(Kip1). A number of complementary approaches allow the demonstration that p57(Kip2) buildup is due to the transcriptional activation of CDKN1C, the p57(Kip2)-encoding gene, while neither p57(Kip2) half-life elongation nor its cell relocalization were observed. We also identified a heretofore undescribed pattern of p57(Kip2) phosphorylated isoforms which, however, did not change in response to STI571 cell treatment. The imatinib-dependent p57(Kip2) upregulation occurs only in STI571-responsive cells, while the CKI accumulation was not evidenced in an imatinib-resistant clone. Nilotinib and dasatinib (second-generation BCR-ABL inhibitors), at concentrations comparable to those used in therapy, increase the CKI but do not affect p271(KiP1) level. Finally, CD34(+) cells from CML patients display a clear imatinib-dependent p57(Kip2) upregulation, which was not observed in CD34(+) cells from control subjects. In conclusion, our study points to p57(Kip2) as a novel and precocious effector of BCR-ABL targeting drugs.