p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation
p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation
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DOI：
10.1016/j.bbrc.2009.04.015
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发表时间：
2009-06-12
影响因子：
3.1
通讯作者：
Murate, T.
中科院分区：
文献类型：
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作者：
Furuhata, A.;Kimura, A.;Murate, T.
Janus kinase2(JAK2)V617F突变被认为是骨髓增生性疾病(MPD)的主要原因。然而，JAK2V617F引起细胞异常生长的机制尚不清楚。本研究利用JAK2V617F-BA/F3和MOCK-BA/F3分析了细胞周期调控蛋白的表达。JAK2V617F-BA/F3，而不是mock-BA/F3，表现出IL-3非依赖的细胞生长和结构性STATS激活。在JAK2V617F-BA/F3细胞中，细胞周期调节因子p27(Kip1)在G1向S的转变中被解除调控，而在模拟对照中未观察到。P27(Kip1)的失控不是由于p27(Kip1)的mRNA水平，而是由于Skp2启动子中的STAT结合而导致泛素E3连接酶的一个亚基Skp2的高表达。与JAK2V617F过表达一样，结构性激活的STAT5或STAT3诱导了BA/F3细胞p27(Kip1)的异常表达。在转BCR/ABL基因的BA/F3细胞中也观察到类似的结果。我们的结果阐明了JAK2V617F通过STAT转录因子调控Skp2基因表达的调控机制。(C)2009 Elsevier Inc.保留所有权利。
Janus kinase 2 (JAK2) V617F mutation has been regarded as the major cause of myeloproliferative disorders (MPD). However, the mechanisms of abnormal cell growth by JAK2V617F have not been elucidated. In this study, cell cycle regulatory protein expression was analyzed using JAK2V617F-Ba/F3 and mock-Ba/F3. JAK2V617F-Ba/F3, but not mock-Ba/F3, showed IL-3 independent cell growth and constitutive STATs activation. Deregulation of p27(Kip1), the cell cycle regulator at the G1 to S transition, was observed in JAK2V617F-Ba/F3 but not in mock-control. p27(Kip1) deregulation was not due to p27(Kip1) mRNA level but due to high Skp2 expression, a subunit Of ubiquitin E3 ligase, through the STAT binding in the Skp2 promoter. Like JAK2V617F overexpression, constitutively active STAT5 or STAT3 induced aberrant p27(Kip1) expression of Ba/F3 cells. Similar findings were observed in BCR/ABL-transfected Ba/F3. Our results elucidate the regulatory mechanism by which JAK2V617F modulates Skp2 gene expression through the STAT transcription factors. (C) 2009 Elsevier Inc. All rights reserved.