Fukuda N, Saitoh M, Kobayashi N, Miyazono K
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Oncogene. 2006 Jun 15;25(25):3509-17. doi: 10.1038/sj.onc.1209393. Epub 2006 Jan 30.
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 3 ng/ml of BMP-4 is sufficient to induce the expression of proapoptotic proteins, puma and bax, in a p53-dependent mechanism, and facilitate Ca(2+) 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.
骨形态发生蛋白（BMP）-4可抑制骨髓瘤细胞的增殖并诱导其凋亡。然而，关于BMP-4引发这种凋亡的分子机制却知之甚少。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，3 ng/ml的BMP-4足以通过p53依赖机制诱导促凋亡蛋白puma和bax的表达，并促进Ca(2+)从内质网释放到细胞质中，从而导致半胱天冬酶-12的激活和内质网功能障碍。与HS-72细胞类似，具有野生型p53基因的多发性骨髓瘤细胞对BMP-4诱导的凋亡的敏感性远高于没有野生型p53基因的细胞，这表明在富含内质网的细胞（如杂交瘤和骨髓瘤细胞）中，BMP-4诱导凋亡过程中内质网功能障碍需要野生型p53状态。这些发现表明，野生型p53基因的存在和内质网的富集决定了对BMP-4有效凋亡的敏感性，并表明内质网应激诱导剂在多发性骨髓瘤治疗中具有重要价值。
