PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression
PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression
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DOI：
10.1038/onc.2010.279
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发表时间：
2010-10-01
期刊：
影响因子：
8
通讯作者：
Loreni, F.
中科院分区：
文献类型：
--
作者：
Iadevaia, V.;Caldarola, S.;Loreni, F.
PIM 1是一种由细胞因子、生长因子和激素调节的组成型活性丝氨酸/苏氨酸激酶。它参与细胞周期进程和细胞凋亡的控制，其过表达与各种淋巴和造血系统恶性肿瘤有关。PIM 1的活性依赖于参与转录、细胞周期和凋亡的几个靶点的磷酸化。我们最近观察到PIM 1与核糖体蛋白（RP）S19相互作用并与核糖体共沉积。核糖体合成缺陷（核糖体应激）已被证明激活p53依赖性生长停滞反应。为了研究PIM 1是否在核糖体应激反应中起作用，我们在TF-1和K562红系细胞系中诱导核糖体合成改变。我们发现，RP缺陷，诱导的RNA干扰或治疗核仁功能的抑制剂，导致了激烈的不稳定的PIM 1。较低水平的PIM 1诱导细胞周期抑制剂p27（Kip 1）的增加，并且即使在不存在p53的情况下也阻断细胞增殖。值得注意的是，通过转染恢复PIM 1水平导致细胞生长恢复。我们的数据表明，PIM 1可以作为一个传感器的核糖体压力独立或与已知的p53依赖性机制。Oncogene（2010）29，5490-5499; doi：10.1038/onc.2010.279; 2010年7月19日在线发表
PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP) S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53-dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27(Kip1) and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms. Oncogene (2010) 29, 5490-5499; doi:10.1038/onc.2010.279; published online 19 July 2010