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The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

Oncogene volume 19, pages 4669–4684 (2000)Cite this article

Abstract

Cell death processes are progressively inactivated during malignant development, in part by loss of tumor suppressors that can promote cell death. The Bin1 gene encodes a nucleocytosolic adaptor protein with tumor suppressor properties, initially identified through its ability to interact with and inhibit malignant transformation by c-Myc and other oncogenes. Bin1 is frequently missing or functionally inactivated in breast and prostate cancers and in melanoma. In this study, we show that Bin1 engages a caspase-independent cell death process similar to type II apoptosis, characterized by cell shrinkage, substratum detachment, vacuolated cytoplasm, and DNA degradation. Cell death induction was relieved by mutation of the BAR domain, a putative effector domain, or by a missplicing event that occurs in melanoma and inactivates suppressor activity. Cells in all phases of the cell cycle were susceptible to death and p53 and Rb were dispensable. Notably, Bin1 did not activate caspases and the broad spectrum caspase inhibitor ZVAD.fmk did not block cell death. Consistent with the lack of caspase involvement, dying cells lacked nucleosomal DNA cleavage and nuclear lamina degradation. Moreover, neither Bcl-2 or dominant inhibition of the Fas pathway had any effect. In previous work, we showed that Bin1 could not suppress cell transformation by SV40 large T antigen. Consistent with this finding, we observed that T antigen suppressed the death program engaged by Bin1. This observation was interesting in light of emerging evidence that T antigen has roles in cell immortalization and human cell transformation beyond Rb and p53 inactivation. In support of a link to c-Myc-induced death processes, AEBSF, a serine protease inhibitor that inhibits apoptosis by c-Myc, potently suppressed DNA degradation by Bin1. Our findings suggest that the tumor suppressor activity of Bin1 reflects engagement of a unique cell death program. We propose that loss of Bin1 may promote malignancy by blunting death penalties associated with oncogene activation.

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Acknowledgements

For providing cDNA clones we thank D Andrews, D Beach, S Frisch, S Nagata, R Press and D Quelle. Support from the Wistar Flow Cytometry Core Facility and the Wistar Cancer Core Grant CA10815 is acknowledged. We thank T Halazonetis, A Oliff, E Routhier and A Muller for critical comments. This work was funded by grants from the US Army Breast Cancer Research Program (DAMD17-96-1-6324) and the American Cancer Society (CN-160). K Elliott was supported by an NIH training grant. K Ge was the recipient of a fellowship award from the Adler Foundation. GC Prendergast is a Pew Scholar in the Biomedical Sciences.

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  1. Kai Ge

    Present address: The Rockefeller University, New York, NY, USA

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  1. The Wistar Institute, Philadelphia, PA, USA

    Katherine Elliott, Kai Ge, Wei Du & George C Prendergast

  2. Glenolden Laboratory, DuPont Pharmaceuticals Company, Glenolden, PA, USA

    Wei Du & George C Prendergast

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Elliott, K., Ge, K., Du, W. et al. The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program. Oncogene 19, 4669–4684 (2000). https://doi.org/10.1038/sj.onc.1203681

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