Bim must be able to engage all pro-survival Bcl-2 family members for efficient tumor suppression.
Bim must be able to engage all pro-survival Bcl-2 family members for efficient tumor suppression.
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DOI：
10.1038/onc.2011.508
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发表时间：
2012-07-12
期刊：
影响因子：
8
通讯作者：
Bouillet, P.
中科院分区：
文献类型：
--
作者：
Merino, D.;Strasser, A.;Bouillet, P.
转录调节因子Myc的过度表达被认为是大量人类淋巴瘤和某些其他癌症发展的原因或促成因素。凋亡性细胞死亡构成肿瘤抑制机制，特别是在Myc过表达的背景下。因此，在Eμ-Myc转基因小鼠中，淋巴瘤的发展，其模拟导致伯基特淋巴瘤的Myc/IgH染色体易位，通过伴随的抗凋亡Bcl-2家族成员的过度表达或仅促凋亡BH 3蛋白如Bim的损失而加速。Bim以高亲和力结合所有促存活Bcl-2样蛋白，并且还可以与Bax/巴克相互作用，但仍不清楚这些相互作用中的哪些对于其肿瘤抑制功能是关键的。我们之前已经产生了敲入突变小鼠，其中Bim的BH 3区域已与Bad、Noxa或Puma的BH 3区域交换，因此它只能结合选择的促生存Bcl-2样蛋白：BimBad结合至Bcl-2、Bcl-xL和Bcl-w，但不结合Mcl-1或A1; BimNoxa仅与Mcl-1和A1结合，作为对照，BimPuma仍然可以结合所有促存活Bcl-2样蛋白。我们现在已经将这些Bim突变小鼠与Eμ-Myc转基因小鼠杂交，并发现BimBad和BimNoxa突变，但不是BimPuma突变，大大加速Myc诱导的淋巴瘤发展并增加白血病负担。这些结果表明，为了获得最佳的肿瘤抑制活性，Bim必须能够与所有而不仅仅是选择促存活Bcl-2家族成员相互作用。
Over-expression of the transcriptional regulator Myc is thought to be the cause or a contributing factor in the development of a large number of human lymphomas and certain other cancers. Apoptotic cell death constitutes a tumor suppressive mechanism, particularly in the context of Myc over-expression. Accordingly, lymphoma development in Eμ-Myc transgenic mice, which mimic the Myc/IgH chromosomal translocation that causes Burkitt Lymphoma, is accelerated by concomitant over-expression of anti-apoptotic Bcl-2 family members or loss of proapoptotic BH3 only proteins, such as Bim. Bim binds with high affinity to all prosurvival Bcl-2-like proteins and can also interact with Bax/Bak, but it remains unclear which of these interactions are critical for its tumor suppressive function. We have previously generated knock-in mutant mice in which the BH3 region of Bim has been exchanged with that for Bad, Noxa or Puma so that it can only bind to select pro-survival Bcl-2-like proteins: BimBad binding to Bcl-2, Bcl-xL and Bcl-w but not Mcl-1 or A1; BimNoxa binding only to Mcl-1 and A1 and as a control, BimPuma, which can still bind all pro-survival Bcl-2-like proteins. We have now inter-crossed these Bim mutant mice with Eμ-Myc transgenic mice and found that both the BimBad and the BimNoxa mutations but not the BimPuma mutation greatly accelerate Myc-induced lymphoma development and increase leukemic burden. These results demonstrate that for optimal tumor suppressive activity, Bim must be able to interact with all and not just select pro-survival Bcl-2 family members.
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影响因子：
64.8
作者：
STRASSER, A;HARRIS, AW;CORY, S
通讯作者：
CORY, S
影响因子：
50.3
作者：
Letai, A;Sorcinelli, MD;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
56.9
作者：
Bouillet, P;Metcalf, D;Strasser, A
通讯作者：
Strasser, A
DOI：
10.1073/pnas.0403286101
发表时间：
2004-06-22
影响因子：
11.1
作者：
Hemann, MT;Zilfou, JT;Lowe, SW
通讯作者：
Lowe, SW
影响因子：
15.9
作者：
Xiang, Zhifu;Luo, Hui;Tomasson, Michael H.
通讯作者：
Tomasson, Michael H.