Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells
Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells
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DOI：
10.1038/sj.onc.1209393
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发表时间：
2006-06-15
期刊：
影响因子：
8
通讯作者：
Miyazono, K.
中科院分区：
文献类型：
--
作者：
Fukuda, N.;Saitoh, M.;Miyazono, K.
骨形态发生蛋白 (BMP)-4 抑制骨髓瘤细胞增殖并诱导其凋亡。然而，人们对 BMP-4 如何执行这种细胞凋亡的分子机制知之甚少。在本报告中，我们研究了 p53 和内质网 (ER) 在 BMP-4 诱导的小鼠杂交瘤 HS-72 细胞凋亡中的作用。我们发现3ng/ml的BMP-4足以以p53依赖性机制诱导促凋亡蛋白puma和bax的表达，并促进Ca2+从ER释放到细胞质，导致caspase-12激活和ER功能障碍。与 HS-72 细胞类似，具有野生型 p53 基因的多发性骨髓瘤细胞比不具有野生型 p53 基因的细胞对 BMP-4 诱导的细胞凋亡表现出更高的敏感性，这表明在富含 ER 的细胞（例如杂交瘤和骨髓瘤细胞）中，在 BMP-4 诱导细胞凋亡期间，ER 功能障碍需要野生型 p53 状态。这些。研究结果表明，野生型 p53 基因的存在和 ER 的富集决定了 BMP-4 对有效细胞凋亡的敏感性，并表明 ER 应激诱导剂在多发性骨髓瘤的治疗中具有重要价值。
Bone morphogenic protein (BMP)-4 inhibits proliferation and induces the apoptosis of myeloma cells. However, little is known about the molecular mechanisms of how BMP-4 executes this apoptosis. In this report, we investigated the roles of p53 and the endoplasmic reticulum (ER) in BMP-4-induced apoptosis of mouse hybridoma HS-72 cells. We found that 3ng/ml of BMP-4 is sufficient to induce the expression of proapoptotic proteins, puma and bax, in a p53-dependent mechanism, and facilitate Ca2+ release from the ER to the cytosol, resulting in the activation of caspase-12 and ER dysfunction. Similarly to HS-72 cells, multiple myeloma cells with wild-type p53 genes show much higher sensitivity to BMP-4-induced apoptosis than cells without wild-type p53 genes, suggesting that wild-type p53 status is required for dysfunction of the ER during BMP-4-induced apoptosis in ER-enriched cells, such as hybridoma and myeloma cells. These. findings demonstrate that the presence of wild-type p53 genes and enrichment of the ER determines the sensitivity to effective apoptosis by BMP-4, and suggest that ER stress-inducing agents would be valuable in the treatment of multiple myeloma.