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Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells

Oncogene volume 25, pages 3509–3517 (2006)Cite this article

Abstract

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 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.

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Abbreviations

TGF-β:

transforming growth factor-β

BMP:

bone morphogenetic protein

ER:

endoplasmic reticulum

UPR:

unfolded protein response

Rh 123:

fluorescence probe dihydrhodamine 123

WST-8:

2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt

Fura-2-AM:

1-[6-amino-2-(5-carboxy-2-oxazolyl)-5-benzofuranyloxy]-2-(2-amino-5-methylphenoxy)-ethane-N,N,N′,N′-tetra acetic acid, penta acetoxymethyl ester

PI:

propidium iodide

TNF-α:

tumor necrosis factor-α

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Acknowledgements

We are grateful to Drs S Nakao and H Sugiya for measuring [Ca2+]i and valuable discussions, and Dr K Takeda for helping with subcellular localization experiments. We also thank Drs K Tobiume, N Tanaka, K Yamato and H Kadowaki for the gift of plasmids, cells and their advice, and all the members of the Molecular Pathology Laboratory and the Biochemistry Laboratory of the Cancer Institute Tokyo for critical comments. This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan (MEXT)

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  1. N Fukuda and M Saitoh: Both these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan

    N Fukuda, M Saitoh, N Kobayashi & K Miyazono

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  1. N Fukuda
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  2. M Saitoh
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Correspondence to K Miyazono.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Fukuda, N., Saitoh, M., Kobayashi, N. et al. Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells. Oncogene 25, 3509–3517 (2006). https://doi.org/10.1038/sj.onc.1209393

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