Anti-apoptotic function of EAT/mcl-1 on diseases

EAT/mcl-1对疾病的抗凋亡作用

• 批准号: 11670192
• 负责人: UMEZAWA Akihiro
• 金额: $ 2.18万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670192/
• 关键词: apoptosis; EAT; mcl-1; islet cell; transgenic mice; differentiation; immediate early gene

Early human embryogenesis is chronicled by a well-regulated sequence of cell differentiation events and is likewise correlated with regulated removal of unnecessary cells by apoptosis. A model of early human embryonic development has been established by the use of embryonal carcinoma (EC) cell lines. NCR-G3 cells were established from a human testicular mixed EC and are able to differentiate into neuronal, myogenic, epithelial as well as the trophectodermal lineage.The mitochondria is an important organelle regulating the early stages of the apoptotic pathway. Bcl-2 related proteins have been shown to localize mainly in the outer mitochondrial membrane and to modulate mitochondrial permeability. These important functions are believed to initiate the apoptotic mechanism. EAT/mcl-1 (EAT), which encodes a bcl-2 related protein, was originally isolated as a gene whose expression is induced at an early stage of differentiation in NCR-G3 cells. It has since been found to inhibit apoptosis un … More der a variety of apoptosis-inducing conditions. The human EAT gene was found to be identical in sequence with mcl-1, a member of the bcl-2 family, which was isolated from a human myeloid leukemia cell line during TPA-induced differentiation into the monocyte/macroahage lineage. The murine orthologue of the EAT gene has also been isolated and has been established to be similarly induced by RA in murine embryonic stem (ES) cells and murine EC cell lines such as TT2, PCC3 and F9. Therefore, EAT functions to enhance cell survival.EAT is also known to be an immediate early gene that has an immediate response box in its 3' untranslated region like other immediate early genes such as c-fos, c-jun and colony stimulation factor-1. This evidence implicates a role for EAT in the cellular differentiation associated with embryogenesis. However, the precise expression pattern and intracellular localization during EC differentiation have not been elucidated. We developed the monoclonal antibody which reacts specifically to EAT and determined the localization of EAT in a human EC cell line. Furthermore, we determined the expression of bcl-2 related proteins in EC cells undergoing differentiation or apoptosis and human embryogenesis. Less

人类早期胚胎发育是由一系列调节良好的细胞分化事件记录的，同样与通过细胞凋亡来调节不必要的细胞的移除有关。利用胚胎癌细胞系建立了人类早期胚胎发育模型。NCR-G3细胞是从人睾丸混合EC中建立的，能够分化为神经细胞、肌源性细胞、上皮细胞和滋养外胚层细胞。线粒体是调节细胞凋亡早期阶段的重要细胞器。BCL-2相关蛋白主要定位于线粒体膜外膜，调节线粒体膜通透性。这些重要的功能被认为启动了细胞凋亡的机制。EAT/MCL-1(EAT)是一种编码bcl2相关蛋白的基因，最初被分离出来是作为一个基因在NCR-G3细胞分化的早期阶段诱导表达。此后，人们发现它能抑制…的细胞凋亡。更多的是在各种诱导凋亡的条件下。人EAT基因序列与BCL-2家族成员MCL-1序列相同，MCL-1是在TPA诱导分化为单核/巨噬细胞系的过程中从人髓系白血病细胞系中分离出来的。EAT基因的小鼠同源基因也已被分离出来，并已被证实在小鼠胚胎干细胞(ES)和小鼠EC细胞系如TT2、PCC3和F9中类似地被RA诱导。因此，EAT具有促进细胞存活的功能。EAT也被认为是一个即刻早期基因，与其他即刻早期基因如c-fos、c-jun和克隆刺激因子-1一样，在其3‘非翻译区有一个即时反应盒。这一证据表明，EAT在与胚胎发生相关的细胞分化中发挥了作用。然而，EC分化过程中确切的表达模式和细胞内定位尚不清楚。我们研制了与EAT特异反应的单抗，并确定了EAT在人EC细胞系中的定位。此外，我们还检测了bcl2相关蛋白在分化或凋亡的EC细胞和人类胚胎发育过程中的表达。较少

项目成果

H.Okita et al .: "Acute myeloid leukemia possessing jumping translocation is related to highly elevated levels of EAT/mcl-1, a Bcl-2 related gene with anti-apoptotic functions"Leukemia Res. 24. 73-77 (2000)

H.Okita 等人：“具有跳跃易位的急性髓性白血病与 EAT/mcl-1 水平的高度升高有关，EAT/mcl-1 是一种具有抗凋亡功能的 Bcl-2 相关基因”Leukemia Res.

Fukuchi, Y., Kizaki, M., Yamato, K., Kawamura, C., Umezawa, A., Hata, J-i., Nishihara, T.and Ikeda, Y.: "Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells."Oncogene. (in press).

Fukuchi, Y.、Kizaki, M.、Yamato, K.、Kawamura, C.、Umezawa, A.、Hata, J-i.、Nishihara, T. 和 Ikeda, Y.：“Mcl-1，一种早期诱导分子

Sano,M.: "Involvement of EAT/mcl-1, an anti-apoptotic bcl-2 related gene, in murine embryogenesis and human development."Cell Res.. 259(1). 127-139 (2000)

Sano,M.：“EAT/mcl-1（一种抗凋亡 bcl-2 相关基因）参与小鼠胚胎发生和人类发育。”Cell Res.. 259(1)。

Sano, M., Umezawa, A., Abe, H., Akatsuka, A., Nonaka, S., Shimizu, H., Fukuma, M., Hata, J-i.: "EAT/mcl-1 expression in the human embryonal carcinoma cells undergoing differetiation and apoptosis."Exp Cell Res. (in press).

Sano, M.、Umezawa, A.、Abe, H.、Akatsuka, A.、Nonaka, S.、Shimizu, H.、Fukuma, M.、Hata, J-i.：“EAT/mcl-1 在人类中的表达

Y.Fukuchi et al.: "Human acute myeloblastic leukemia-ascites model using the human GM-CSF and IL-3-releasing transgenic SCID mice"Ann. Hematol.. 78. 223-231 (1999)

Y.Fukuchi 等人：“使用人 GM-CSF 和释放 IL-3 的转基因 SCID 小鼠建立人急性髓细胞性白血病腹水模型”Ann.