Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7.
Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7.
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DOI：
10.1371/journal.pone.0125982
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Imaizumi K
中科院分区：
文献类型：
--
作者：
Iwamoto H;Matsuhisa K;Saito A;Kanemoto S;Asada R;Hino K;Takai T;Cui M;Cui X;Kaneko M;Arihiro K;Sugiyama K;Kurisu K;Matsubara A;Imaizumi K
BBF 2 H7是内质网（ER）驻留的跨膜碱性亮氨酸拉链（bZIP）转录因子，其响应于ER应激通过调节的膜内蛋白水解在跨膜结构域被切割。含有转录激活和bZIP结构域的裂解的细胞质N-末端易位到细胞核中以促进靶基因的表达。在软骨细胞中，裂解的管腔C-末端被细胞外分泌，并通过激活Hedgehog信号转导促进邻近细胞的增殖。在本研究中，我们发现，Bbf 2 h7表达水平显着增加了1.070-2.567倍，在几种肿瘤类型，包括胶质母细胞瘤相比，在各自的正常组织，使用ONCOMINE癌症分析数据库。在一些Hedgehog配体依赖性癌细胞系（包括胶质母细胞瘤U251 MG细胞）中，BBF 2 H7 C-末端从细胞分泌到培养基中，并通过激活Hedgehog信号传导促进癌细胞增殖。Bbf 2 h7表达的下调通过下调Hedgehog信号抑制U251 MG细胞的增殖。通过向Bbf 2 h7敲低的U251 MG细胞的培养基中添加BBF 2 H7 C-末端来恢复受损的细胞增殖和Hedgehog信号传导。这些数据表明，分泌的管腔BBF 2 H7 C-末端通过激活Hedgehog信号传导参与Hedgehog配体依赖性癌细胞增殖。因此，BBF 2 H7的C-末端可能是一个新的抗癌药物开发的目标。
BBF2H7 is an endoplasmic reticulum (ER)-resident transmembrane basic leucine zipper (bZIP) transcription factor that is cleaved at the transmembrane domain by regulated intramembrane proteolysis in response to ER stress. The cleaved cytoplasmic N-terminus containing transcription activation and bZIP domains translocates into the nucleus to promote the expression of target genes. In chondrocytes, the cleaved luminal C-terminus is extracellularly secreted and facilitates proliferation of neighboring cells through activation of Hedgehog signaling. In the present study, we found that Bbf2h7 expression levels significantly increased by 1.070–2.567-fold in several tumor types including glioblastoma compared with those in respective normal tissues, using the ONCOMINE Cancer Profiling Database. In some Hedgehog ligand-dependent cancer cell lines including glioblastoma U251MG cells, the BBF2H7 C-terminus was secreted from cells into the culture media and promoted cancer cell proliferation through activation of Hedgehog signaling. Knockdown of Bbf2h7 expression suppressed the proliferation of U251MG cells by downregulating Hedgehog signaling. The impaired cell proliferation and Hedgehog signaling were recovered by addition of BBF2H7 C-terminus to the culture medium of Bbf2h7-knockdown U251MG cells. These data suggest that the secreted luminal BBF2H7 C-terminus is involved in Hedgehog ligand-dependent cancer cell proliferation through activation of Hedgehog signaling. Thus, the BBF2H7 C-terminus may be a novel target for the development of anticancer drugs.
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影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
21.3
作者：
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Imaizumi, Kazunori
影响因子：
5.3
作者：
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Imaizumi, Kazunori
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Charron, Frederic
影响因子：
64.5
作者：
Denef, N;Neubüser, D;Cohen, SM
通讯作者：
Cohen, SM