MCL－1在BCL／ABL抗凋亡信号传导中的作用

To investigate the effect of STI571, an inhibitor of tyrosine kinase, on the proliferation and apoptosis of chronic myelogenous leukemia (CML) cells and the possible apoptosis-inducing mechanism, and also to investigate the possible targeted genes that regulated by the signaling transduction pathways of BCR/ABL , and the effect of these pathways on the biologic functions of CML cells. Methods K562 cell line was used to observe the effect of tyrosine kinase inhibitor STI571 and specific inhibitors of PI3K and MAPK on CML cells. Proliferation and cytotoxity were analyzed by MTT assay. The apoptoic cells were labelled with Annexin V-FITC and PI and then analyzed by flow cytometry. The expression of apoptotic-related proteins in K562 cell were determined by western blotting with specific antibodies. Results STI571 can significantly inhibit the proliferation and induce apoptosis of K562 cells in a dose and time-dependent way. Coincidently, the protein phosphorylation on tyrosine residues is reduced and the expression of anti-apoptotic protein Mcl-1 and Bcl-xl are down-regulated after exposure to STI571. Inhibition of MAPK or PI3-Kinase pathways can inhibit the proliferation of K562 cells but cannot induce apoptosis significantly. However, the suppression of proliferation was more pronounced and apoptosis of K562 cells could be induced when inhibited these two pathways simultaneously. The expressions of both Mcl-1 and Bcl-xl were down-regulated after inhibiting the signal transduction pathways, this coincidences with the level of the growth inhibition and apoptosis Conclusions STI571 can induce the apoptosis of CML cells through down-regulating the expression of Mcl-1 and Bcl-xl. These two gene expressions are regulated by the down-stream pathways of BCR/ABL. This may be responsible for the anti-apoptotic mechanism of CML cells and suggests that Mcl-1 and Bcl-xl may play an important role in anti-apoptotic process of CML cells.

慢性髓性白血病（CML）是由增强BCR/ABL酪氨酸活性进而激活下游信号传导途径并抑制细胞凋亡所致。本研究拟通过阻断BCR/ABL下游信号传导途径观察对CML细胞增殖和凋亡以及对Mcl-1等抗凋亡基因表达的影响，阐明MCL-1 在BCR/ABL抗凋亡信号传导中的作用和地位，MCL闹瘟铺峁├砺刍〔⑻剿餍碌姆椒ā