The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells
The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells
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DOI：
10.1002/eji.200424981
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发表时间：
2004-11-01
影响因子：
5.4
通讯作者：
Amiot, M
中科院分区：
文献类型：
--
作者：
Gomez-Bougie, P;Bataille, R;Amiot, M
多发性骨髓瘤是一种致命的B细胞恶性肿瘤，其特征在于骨髓内浆细胞的积聚。IL-6是骨髓瘤细胞的主要存活因子。Bcl-2蛋白家族调节细胞凋亡的途径，这些途径在生长因子缺乏时被激活。仅具有单个Bcl-2同源结构域（仅BH 3）的促凋亡蛋白是凋亡的有效诱导剂。在骨髓瘤细胞中，Mcl-1已被证明是一种主要的抗凋亡蛋白，似乎通过JAK/STAT途径调节细胞存活。在这项研究中，我们研究了BH 3-only蛋白Birn的调节及其与Mcl-1的相互作用。三种主要的Birn同种型在骨髓瘤细胞中表达，并受IL-6负调控。IL-6信号传导的阻断诱导Birn的上调伴随Mcl-1的下调。主要的兴趣，Bim被发现与Mcl-1在活的骨髓瘤细胞，而这种相互作用被破坏的细胞凋亡诱导。值得注意的是，虽然Birn也被发现与Bcl-2强烈相关，但这种相互作用在凋亡诱导下不会改变。因此，在骨髓瘤细胞中，Mcl-1通过复合物形成中和Birn，从而防止细胞凋亡。在凋亡诱导下，Mcl-1的消失允许Birn行使其促凋亡功能并激活Bax。
Multiple myeloma is a fatal B cell malignancy characterized by the accumulation of plasma cells within the bone marrow. IL-6 is a major survival factor for myeloma cells. BcI-2 protein family regulates pathways to apoptosis that are activated upon growth factor deprivation. Pro-apoptotic proteins that have only a single Bcl-2 homology domain, BH3-only, are potent inducers of apoptosis. In myeloma cells, Mcl-1 has been shown to be a major anti-apoptotic protein that appears to regulate cell survival through the JAK/STAT pathway. In this study, we examined the regulation of the BH3-only protein Birn and its interaction with Mcl-1. The three major Birn isoforms are expressed in myeloma cells and are negatively regulated by IL-6. Blockade of IL-6 signaling induces an up-regulation of Birn concomitant to Mcl-1 downregulation. Of major interest, Bim is found strongly associated with Mcl-1 in viable myeloma cells while this interaction is disrupted under apoptosis induction. Of note, while Birn is also found strongly associated to Bcl-2, this interaction is not changed under apoptosis induction. Thus, in myeloma cells, Mcl-1 neutralizes Birn through complex formation and therefore prevents apoptosis. Under apoptosis induction, the disappearance of Mcl-1 allows Birn to exercise its pro-apoptotic function and to activate Bax.