Herbal Research Laboratory, Food Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Post Box No. 80, Mahatma Gandhi Marg, Lucknow 226001, India.
Herbal Research Laboratory, Food Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Post Box No. 80, Mahatma Gandhi Marg, Lucknow 226001, India; Academy of Scientific and Innovative Research, CSIR-IITR, Lucknow campus, India.
Eur J Cell Biol. 2017 Dec;96(8):728-738. doi: 10.1016/j.ejcb.2017.09.002. Epub 2017 Sep 23.
BH3-only proteins constitute major proportion of pro-apoptotic members of B-cell lymphoma 2 (Bcl-2) family of apoptotic regulatory proteins and participate in embryonic development, tissue homeostasis and immunity. Absence of BH3-only proteins contributes to autoimmune disorders and tumorigenesis. Bim (Bcl-2 Interacting Mediator of cell death), most important member of BH3-only proteins, shares a BH3-only domain (9-16 aa) among 4 domains (BH1-BH4) of Bcl-2 family proteins and highly pro-apoptotic in nature. Bim initiates the intrinsic apoptotic pathway under both physiological and patho-physiological conditions. Reduction in Bim expression was found to be associated with tumor promotion and autoimmunity, while overexpression inhibited tumor growth and drug resistance as cancer cells suppress Bim expression and stability. Apart from its role in normal homeostasis, Bim has emerged as a central player in regulation of tumorigenesis, therefore gaining attention as a plausible target for chemotherapy. Regulation of Bim expression and stability is complicated and regulated at multiple levels viz. transcriptional, post-transcriptional, post-translational (preferably by phosphorylation and ubiquitination), epigenetic (by promoter acetylation or methylation) including miRNAs. Furthermore, control over Bim expression and stability may be exploited to enhance chemotherapeutic efficacy, overcome drug resistance and select anticancer drug regimen as various chemotherapeutic agents exploit Bim as an executioner of cell death. Owing to its potent anti-tumorigenic activity many BH3 mimetics e.g. ABT-737, ABT-263, obatoclax, AT-101and A-1210477 have been developed and entered in clinical trials. It is more likely that in near future strategies commanding Bim expression and stability ultimately lead to Bim based therapeutic regimen for cancer treatment.
BH3- 仅蛋白构成 B 细胞淋巴瘤 2 (Bcl-2) 细胞凋亡调节蛋白家族中促凋亡成员的主要比例，并参与胚胎发育、组织稳态和免疫。BH3- 仅蛋白的缺失导致自身免疫疾病和肿瘤发生。Bim（Bcl-2 相互作用介导细胞死亡的介质）是 BH3- 仅蛋白的最重要成员，在 Bcl-2 家族蛋白的 4 个结构域（BH1-BH4）中共享 BH3- 仅结构域（9-16 aa），具有高度的促凋亡特性。Bim 在生理和病理生理条件下启动内在凋亡途径。研究发现，Bim 表达减少与肿瘤促进和自身免疫有关，而过度表达则抑制肿瘤生长和耐药性，因为癌细胞抑制 Bim 表达和稳定性。除了在正常稳态中的作用外，Bim 已成为肿瘤发生调节的核心参与者，因此作为化疗的合理靶点引起关注。Bim 表达和稳定性的调节很复杂，可在多个水平上进行调节，如转录、转录后、翻译后（最好通过磷酸化和泛素化）、表观遗传（通过启动子乙酰化或甲基化），包括 miRNAs。此外，控制 Bim 的表达和稳定性可能被用来增强化疗疗效、克服耐药性并选择抗癌药物方案，因为各种化疗药物将 Bim 作为细胞死亡的执行者。由于其强大的抗肿瘤活性，许多 BH3 模拟物如 ABT-737、ABT-263、obatoclax、AT-101 和 A-1210477 已被开发并进入临床试验。在不久的将来，更有可能的是，控制 Bim 表达和稳定性的策略最终导致基于 Bim 的癌症治疗方案。
