Anti-myeloma activity of members of the TGF-β family with induction of growth arrest and apoptosis^*

TGF-β 家族成员的抗骨髓瘤活性，诱导生长停滞和细胞凋亡^*

基本信息

批准号：
12557157
负责人：
YAMATO Kenji
金额：
$ 5.31万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557157/
关键词：
TGF-β BMP-2 myeloma apoptosis p21 G1 arrest TGFβ アポトーシス

项目摘要

Bone morphogenetic proteins (BMPs) , members of the transforming growth factor (TGF)-β super family, are multifunctional cytokines. We show in this study that BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPM1 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 ceHs), but also in primary samples from 6 patients with multiple myeloma. BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells, which was associated with up-regulation of cyclin-dependent kinase inhibitors [p21^<CIP1/WAP1> (p21) and p27^<Kip1>] , hypophosphorylation of retinoblastoma (Rb) protein and down-regulation of Bc1-X_L, an anti-apoptotic molecule. Analysis of p21 promoter in HS-72 mouse plasmacytic cells revealed that BMP-2 induced expression of p21 at the level of transcription and that a 29-base pair <b) region of the p21 promoter (-1928/-1900 relative to the TATA box) , conserved between mice and humans, contained a binding sequence for Smad4 and Smad1 and was respons … More ible for activation of the promoter by BMP-2.We investigated the effects of increased level of p21 on cell cycle and viability using an ecdysone-inducible p21 expression clones of HS-72 cells. Ponasterone A (an analog of ecdysone)-induced accumulation of p21 resulted in the cell cycle arrest in the G1 phase as was observed in BMP-2-treated HS-72 cells. Increased p21 did not cause apoptotic cell death by 48 h after ponasterone A treatment, but initiated cell death after 4 days exposure. These results suggested that expression of p21 is responsible for BMP-2-induced G1 arrest, but not for BMP-2-induced apoptosis and that sustained expression of p21 decreases cell viability through apoptotic process.From these observation, we conclude that BMP-2 would be useful as a novel therapeutic agent in the treatment of multiple myeloma both by means of its antitumor effect of inducing apoptotis and through its original bone-inducing activity, because bone lesions are frequently seen in myeloma patients. Less

骨形态发生蛋白 (BMP) 是转化生长因子 (TGF)-β 超家族的成员，是多功能细胞因子，我们在这项研究中表明，BMP-2 不仅在人骨髓瘤细胞系（U266、RPM1 8226、HS）中诱导细胞凋亡。 -Sultan、IM-9、OPM-2 和 KMS-12 细胞），而且还存在于 6 名多发性骨髓瘤患者的原始样本中。 BMP-2 导致细胞周期停滞在 G1 期以及随后的骨髓瘤细胞凋亡，这与细胞周期蛋白依赖性激酶抑制剂的上调有关 [p21^<CIP1/WAP1> (p21) 和 p27^<Kip1> ]、视网膜母细胞瘤 (Rb) 蛋白的低磷酸化和 Bc1-X_L（一种抗凋亡分子）的下调。 p21 启动子的分析。 HS-72小鼠浆细胞显示BMP-2在转录水平上诱导p21的表达，并且p21启动子的29碱基对<b)区域（相对于TATA盒-1928/-1900）在小鼠和人类，含有 Smad4 和 Smad1 的结合序列，并且能够响应 BMP-2 激活启动子。我们研究了 p21 水平增加的影响使用 HS-72 细胞的蜕皮激素诱导性 p21 表达克隆来观察细胞周期和活力，Ponasterone A（蜕皮激素类似物）诱导的 p21 积累导致细胞周期停滞在 G1 期，如 BMP-2- 中所观察到的。 HS-72 细胞。在 ponasterone A 处理后 48 小时，p21 的增加并未导致细胞凋亡，但在暴露 4 天后开始细胞死亡。结果表明，p21 的表达负责 BMP-2 诱导的 G1 期阻滞，但不负责 BMP-2 诱导的细胞凋亡，并且 p21 的持续表达通过细胞凋亡过程降低细胞活力。根据这些观察，我们得出结论，BMP-2 会由于其诱导细胞凋亡的抗肿瘤作用和其原始的骨诱导活性，可用作治疗多发性骨髓瘤的新型治疗剂，因为骨病变在骨髓瘤患者中常见。