| Co-Investigator(Kenkyū-buntansha) |
ETO Yuzuru Ajinomoto Co., Central Research Laboratories, Laboratory Head, 医薬研究所・創薬研究所, 主席研究員
KIZAKI Masahiro Keio University, School of Medicine, Lecturer, 医学部, 講師 (20161432)
NISHIHARA Tatsuji Kyushu Dental College, Professor, 歯学部, 教授 (80192251)
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| Research Abstract |
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
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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
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