BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis.
BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis.
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DOI：
10.1038/cddis.2014.568
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发表时间：
2015-01-22
影响因子：
9
通讯作者：
Nakagawara A
中科院分区：
文献类型：
--
作者：
Tatsumi Y;Takano R;Islam MS;Yokochi T;Itami M;Nakamura Y;Nakagawara A
BNIP 2和Cdc 42 GAP同源（BCH）基序的分子在羧基末端区域1（BMCC 1）基因是高表达的患者有利的神经母细胞瘤（NB）。它编码一个340 kDa的蛋白质，具有保守的BCH支架结构域，可以调节信号网络和多种细胞功能，包括凋亡。在这项研究中，我们确定了BMCC 1促进人NB和非NB细胞凋亡的机制，因为BMCC 1通常在各种器官中表达，特别是在神经元和上皮组织中。我们在这份报告中表明，BMCC 1是由DNA损伤诱导的，DNA损伤是内在凋亡的触发因素之一。因此，我们研究了BMCC 1表达是否影响细胞内信号通过其C-末端区域含有BCH支架结构域的细胞凋亡调控。BMCC 1降低AKT及其上游激酶PDK 1上的存活信号的磷酸化。BMCC 1的上调与叉头盒-O3 a（FOXO 3a）（一种凋亡的下游诱导物，被AKT抑制）的激活和BCL 2抑制剂BIM的诱导相关，表明BMCC 1负调节AKT的磷酸化途径，导致凋亡。此外，我们发现BMCC 1的BNIP 2同源区与BCL 2相互作用。DNA损伤诱导的内源性凋亡通过BMCC 1过表达而增强，并且通过BMCC 1敲低而减弱。综上所述，我们得出结论，BMCC 1促进AKT介导的生存信号通路中的多个步骤的凋亡。这些步骤包括与BCL 2的物理相互作用以及减弱AKT依赖性对FOXO 3a功能的抑制，例如BIM的转录诱导和DNA损伤后毛细血管扩张性共济失调突变（ATM）的磷酸化。我们认为，BMCC 1表达的下调，这是经常观察到的不利NB和上皮来源的癌症，可能会促进肿瘤的发展，废除DNA损伤修复和细胞凋亡。
BNIP2 and Cdc42GAP homology (BCH) motif-containing molecule at the carboxyl-terminal region 1 (BMCC1) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple cellular functions, including apoptosis. In this study, we determined the mechanism by which BMCC1 promotes apoptosis in human NB and non-NB cells, as BMCC1 is normally expressed in various organs, particularly in neuronal and epithelial tissues. We demonstrated in this report that BMCC1 was induced by DNA damage, one of the triggers of intrinsic apoptosis. Accordingly, we investigated whether BMCC1 expression impacts intracellular signals in the regulation of apoptosis via its C-terminal region containing BCH scaffold domain. BMCC1 decreased phosphorylation of survival signals on AKT and its upstream kinase PDK1. BMCC1 upregulation was correlated with the activation of forkhead box-O3a (FOXO3a) (a downstream inducer of apoptosis, which is suppressed by AKT) and induction of BCL2 inhibitor BIM, suggesting that BMCC1 negatively regulates phosphorylation pathway of AKT, resulted in apoptosis. In addition, we found that BNIP2 homology region of BMCC1 interacts with BCL2. Intrinsic apoptosis induced by DNA damage was enhanced by BMCC1 overexpression, and was diminished by knockdown of BMCC1. Taken together, we conclude that BMCC1 promotes apoptosis at multiple steps in AKT-mediated survival signal pathway. These steps include physical interaction with BCL2 and attenuation of AKT-dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia-mutated (ATM) after DNA damage. We propose that downregulation of BMCC1 expression, which is frequently observed in unfavorable NB and epithelial-derived cancers, may facilitate tumor development by abrogating DNA damage repair and apoptosis.