Wang Tao, Xia Dajing, Li Nan, Wang Chunmei, Chen Taoyong, Wan Tao, Chen Guoyou, Cao Xuetao
Institute of Immunology, Zhejiang University, Hangzhou 310031, China and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
J Biol Chem. 2005 Feb 11;280(6):4374-82. doi: 10.1074/jbc.M408708200. Epub 2004 Nov 29.
Genes encoding growth-inhibitory proteins are postulated to be candidate tumor suppressors. The identification of such proteins may benefit the early diagnosis and therapy of tumors. Here we report the cloning and functional characterization of a novel human bone marrow stromal cell (BMSC)-derived growth inhibitor (BDGI) by large scale random sequencing of a human BMSC cDNA library. Human BDGI cDNA encodes a 477-amino acid residue protein that shares high homology with rat and mouse pregnancy-induced growth inhibitors. The C-terminal of BDGI is identical to a novel human pregnancy-induced growth inhibitor, OKL38. BDGI is also closely related to many other eukaryotic proteins, which together form a novel and highly conserved family of BDGI-like proteins. BDGI overexpression inhibits the proliferation, decreases anchorage-dependent growth, and reduces migration of MCF-7 human breast cancer cells, whereas down-regulation of BDGI expression promotes the proliferation of MCF-7 and HeLa cervix epitheloid carcinoma cells. Interestingly, the inhibitory effect of BDGI on MCF-7 cells is more potent than that of OKL38. We demonstrate that BDGI induces cell cycle arrest in S phase and subsequent apoptosis of MCF-7 cells, which is likely to account for the antiproliferative effects of BDGI. This process may involve up-regulation of p27Kip1 and down-regulation of cyclin A, Bcl-2, and Bcl-xL. The inhibitory effect of BDGI on cell proliferation and the induction of apoptosis were also observed in A549 lung cancer cells but not HeLa cells. These results indicate that BDGI might be a growth inhibitor for human tumor cells, especially breast cancer cells, possibly contributing to the development of new therapeutic strategies for breast cancer.
编码生长抑制蛋白的基因被认为是候选肿瘤抑制因子。此类蛋白的鉴定可能有助于肿瘤的早期诊断和治疗。在此，我们通过对人骨髓基质细胞（BMSC）cDNA文库进行大规模随机测序，报告了一种新型人骨髓基质细胞衍生生长抑制剂（BDGI）的克隆及功能特性。人BDGI cDNA编码一种由477个氨基酸残基组成的蛋白，该蛋白与大鼠和小鼠妊娠诱导的生长抑制剂具有高度同源性。BDGI的C末端与一种新型人妊娠诱导生长抑制剂OKL38相同。BDGI还与许多其他真核蛋白密切相关，它们共同构成了一个新的高度保守的BDGI样蛋白家族。BDGI的过表达抑制MCF-7人乳腺癌细胞的增殖，降低其锚定依赖性生长，并减少其迁移，而BDGI表达的下调则促进MCF-7和HeLa宫颈上皮样癌细胞的增殖。有趣的是，BDGI对MCF-7细胞的抑制作用比OKL38更强。我们证明BDGI诱导MCF-7细胞在S期发生细胞周期阻滞并随后凋亡，这可能是BDGI产生抗增殖作用的原因。这个过程可能涉及p27Kip1的上调以及细胞周期蛋白A、Bcl-2和Bcl-xL的下调。在A549肺癌细胞中也观察到了BDGI对细胞增殖的抑制作用和对凋亡的诱导作用，但在HeLa细胞中未观察到。这些结果表明，BDGI可能是人类肿瘤细胞尤其是乳腺癌细胞的生长抑制剂，可能有助于开发新的乳腺癌治疗策略。
