Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines
Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines
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DOI：
10.1182/blood.v96.5.1933.h8001933_1933_1939
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发表时间：
2000-09-01
期刊：
影响因子：
20.3
通讯作者：
Aulitzky, WE
中科院分区：
文献类型：
--
作者：
Jonuleit, T;van der Kuip, H;Aulitzky, WE
慢性粒细胞白血病（CML）是一种恶性干细胞疾病，其特征在于表达组成性激活的Bcr-Abl激酶的髓系祖细胞扩增，这种致癌事件导致细胞凋亡和细胞周期进展的失调。尽管CML细胞凋亡的分子机制已被很好地描述，但细胞周期调控事件仍知之甚少。细胞周期蛋白依赖性激酶p27的抑制剂在造血细胞的生长因子依赖性增殖的调节中起核心作用。因此，我们分析了Bcr-Abl在各种造血细胞系统中对p27表达的调节作用。在小鼠Ba/F3细胞和人M07细胞中，一种活性Bcr-Abl激酶引起p27表达的下调，在生长因子撤除和血清减少后，Bcr-Abl阻断p27表达的上调。此外，在Bcr-Abl阳性M07/p210细胞中，转化生长因子-β（TGF-β）对p27的诱导作用被完全阻断。Bcr-Abl激酶抑制剂可完全消除Bcr-Abl对Ba/F3细胞中p27的下调作用，而Bcr-Abl激酶抑制剂可完全消除Bcr-Abl对Ba/F3细胞中p27的下调作用。Bcr-Abl对p27的下调依赖于蛋白酶体的降解，并可被lactacystin阻断。野生型p27过表达部分拮抗Bcr-Abl诱导的Ba/F3细胞增殖我们的结论是，Bcr-Abl通过干扰细胞周期抑制蛋白p27的调节，促进细胞周期进程和细胞周期蛋白依赖性激酶的激活，（C）2000年由美国血液学会。
Chronic myeloid leukemia (CML) is a malignant stem cell disease characterized by an expansion of myeloid progenitor cells expressing the constitutively activated Bcr-Abl kinase, This oncogenic event causes a deregulation of apoptosis and cell cycle progression. Although the molecular mechanisms protecting from apoptosis in CML cells are well characterized, the cell cycle regulatory event is poorly understood. An inhibitor of the cyclin-dependent kinases, p27, plays a central role in the regulation of growth factor dependent proliferation of hematopoietic cells. Therefore, we have analyzed the influence of Bcr-Abl in the regulation of p27 expression in various hematopoietic cell systems, An active Bcr-Abl kinase causes down-regulation of p27 expression in murine Ba/F3 cells and human M07 cells, Bcr-Abl blocks up-regulation of p27 after growth factor withdrawal and serum reduction. In addition, p27 induction by transforming growth factor-beta (TGF-beta) is completely blocked in Bcr-Abl positive M07/p210 cells. This deregulation is directly mediated by the activity of the Bcr-Abl kinase, A Bcr-Abl kinase inhibitor completely abolishes p27 down-regulation by Bcr-Abl in both Ba/F3 cells transfected either with a constitutively active Bcr-Abl or with a temperature sensitive mutant. The down-regulation of p27 by Bcr-Abl depends on proteasomal degradation and can be blocked by lactacystin. Overexpression of wild-type p27 partially antagonizes Bcr-Abl-induced proliferation in Ba/F3 cells. We conclude that Bcr-Abl promotes cell cycle progression and activation of cyclin-dependent kinases by interfering with the regulation of the cell cycle inhibitory protein p27,(C) 2000 by The American Society of Hematology.