Targeting Bcl-2 based on the interaction of its BH4 domain with the inositol 1,4,5-trisphosphate receptor.
Targeting Bcl-2 based on the interaction of its BH4 domain with the inositol 1,4,5-trisphosphate receptor.
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DOI：
10.1016/j.bbamcr.2008.10.015
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发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
Distelhorst CW
中科院分区：
文献类型：
--
作者：
Rong YP;Barr P;Yee VC;Distelhorst CW
Bcl-2是凋亡调节蛋白大家族的创始成员。Bcl-2是新疗法的主要靶标，因为它在许多形式的癌症中升高，并且基于其抑制细胞凋亡的能力而有助于癌症进展和治疗抗性。Bcl-2与Bcl-2家族的促凋亡成员相互作用以抑制凋亡，并且破坏这种相互作用的小分子已经进入癌症治疗竞技场。Bcl-2的另一个功能是抑制促进细胞凋亡的Ca 2+信号。该功能通过Bcl-2 BH 4结构域与肌醇1，4，5-三磷酸受体（IP 3R）Ca 2+通道的相互作用介导。这种相互作用的一种新的肽抑制剂增强了促凋亡的Ca 2+信号。在初步实验中，该肽增强ABT-737诱导的慢性淋巴细胞白血病细胞凋亡。这些发现引起了人们对BH 4结构域作为潜在治疗靶点的关注。本文综述了Bcl-2的BH 4结构域及其与IP 3R和其他蛋白的相互作用，以及BH 4结构域在Bcl-2抗凋亡功能中的作用。此外，我们推测Bcl-2的BH 4结构域如何不仅可以治疗与凋亡抗性相关的疾病，而且还可以治疗与加速细胞死亡相关的疾病。
Bcl-2 is the founding member of a large family of apoptosis regulating proteins. Bcl-2 is a prime target for novel therapeutics because it is elevated in many forms of cancer and contributes to cancer progression and therapy resistance based on its ability to inhibit apoptosis. Bcl-2 interacts with proapoptotic members of the Bcl-2 family to inhibit apoptosis and small molecules that disrupt this interaction have already entered the cancer therapy arena. A separate function of Bcl-2 is to inhibit Ca2+ signals that promote apoptosis. This function is mediated through interaction of the Bcl-2 BH4 domain with the inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel. A novel peptide inhibitor of this interaction enhances proapoptotic Ca2+ signals. In preliminary experiments this peptide enhanced ABT-737 induced apoptosis in chronic lymphocytic leukemia cells. These findings draw attention to the BH4 domain as a potential therapeutic target. This review summarizes what is currently known about the BH4 domain of Bcl-2, its interaction with the IP3R and other proteins, and the part it plays in Bcl-2’s anti-apoptotic function. In addition, we speculate on how the BH4 domain of Bcl-2 can be targeted therapeutically not only for diseases associated with apoptosis resistance, but also for diseases associated with accelerated cell death.
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