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），转化生长因子（TGF）-β超级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-Sultan，IM-9，IM-9，OPM-2和KMS-12 CEHS）中诱导凋亡，而且在6例患有多发性骨髓瘤患者的主要样本中。 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抗凋亡分子。 HS-72小鼠浆细胞中p21启动子的分析表明，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（-1928/-1900相对于TATA相对于TATA框）包含小鼠和人类之间的启动者的更多IM1和Smad1和Smad的启动者，该序列构成了IM1和Smad4和Smad4。通过BMP-2。我们使用了HS-72细胞的Ecdysone诱导的P21表达克隆，研究了P21水平增加对细胞周期和活力的影响。在BMP-2处理的HS-72细胞中观察到了Ponasterone A（Ecdysone的类似物）诱导的P21积累，导致G1相的细胞周期停滞。 P21增加在Ponasterone治疗后48小时不会导致凋亡细胞死亡，但在暴露4天后会引发细胞死亡。这些结果表明，p21的表达负责BMP-2诱导的G1凋亡，并且持续的p21表达通过凋亡过程降低了细胞活力。从这些观察结果中，我们包括BMP-2在多发性造成骨骼的抗蛋白瘤中，因为其骨骼的抗蛋白质的效果，因为它的骨骼效应是骨骼的，因为它是一种新颖的热药，因为它的骨骼效应是骨骼的肿瘤，因为它是骨骼的作用，因为它是骨骼的骨骼效应。骨髓瘤患者。较少的