Jonuleit T, van der Kuip H, Miething C, Michels H, Hallek M, Duyster J, Aulitzky W E
Dr Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany.
Blood. 2000 Sep 1;96(5):1933-9.
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. (Blood. 2000;96:1933-1939)
慢性粒细胞白血病（CML）是一种恶性干细胞疾病，其特征是表达组成型激活的Bcr-Abl激酶的髓系祖细胞扩增。这一致癌事件导致细胞凋亡和细胞周期进程失调。尽管在CML细胞中保护细胞免于凋亡的分子机制已得到充分表征，但对细胞周期调控事件却知之甚少。细胞周期蛋白依赖性激酶的抑制剂p27在造血细胞生长因子依赖性增殖的调控中起核心作用。因此，我们分析了Bcr-Abl在各种造血细胞系统中对p27表达调控的影响。活性Bcr-Abl激酶可导致小鼠Ba/F3细胞和人M07细胞中p27表达下调。Bcr-Abl可阻断生长因子撤除和血清减少后p27的上调。此外，在Bcr-Abl阳性的M07/p210细胞中，转化生长因子-β（TGF-β）诱导的p27完全被阻断。这种失调是由Bcr-Abl激酶的活性直接介导的。Bcr-Abl激酶抑制剂可完全消除在转染了组成型活性Bcr-Abl或温度敏感突变体的Ba/F3细胞中Bcr-Abl对p27的下调作用。Bcr-Abl对p27的下调作用依赖于蛋白酶体降解，并且可被乳胞素阻断。野生型p27的过表达可部分拮抗Ba/F3细胞中Bcr-Abl诱导的增殖。我们得出结论，Bcr-Abl通过干扰细胞周期抑制蛋白p27的调控来促进细胞周期进程和细胞周期蛋白依赖性激酶的激活。（《血液》。2000年；96:1933 - 1939）
