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Caspase-dependent processing activates the proapoptotic activity of deleted in breast cancer-1 during tumor necrosis factor-alpha-mediated death signaling

Oncogene volume 24, pages 4908–4920 (2005)Cite this article

Abstract

Deleted in breast cancer-1 (DBC-1) was initially cloned from a homozygously deleted region in breast and other cancers on human chromosome 8p21, although no function is known for the protein product it encodes. We identified the generation of amino-terminally truncated versions of DBC-1 during tumor necrosis factor (TNF)-α-mediated apoptosis. Full-length 150 kDa DBC-1 underwent caspase-dependent processing during TNF-α-mediated death signaling, to produce p120 DBC-1 and p66 DBC-1 carboxy-terminal fragments. Endogenous DBC-1 localized to the nucleus in healthy cells, but localized to the cytoplasm during TNF-α-mediated apoptosis, consistent with the loss of the amino-terminus containing the nuclear localization signal. Overexpression of an amino-terminal truncated DBC-1, resembling p120 DBC-1, caused mitochondrial clustering, mitochondrial matrix condensation, and sensitized cells to TNF-α-mediated apoptosis. The carboxy-terminal coiled-coil domain of DBC-1 was responsible for the cytoplasmic and mitochondrial localization, and for the death-promoting activity of DBC-1. Thus, caspase-dependent processing of DBC-1 may act as a feed-forward mechanism to promote apoptosis and possibly also tumor suppression. DBC-1, like its homolog cell cycle and apoptosis regulatory protein-1 (CARP-1), may function in the regulation of apoptosis.

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Acknowledgements

We thank Dr Kyriakos Economides for help with confocal microscopy. We also thank Dr Deirdre Nelson for critical reading, and Thomasina Sharkey for assistance with preparation of the manuscript. This work has been supported by a grant from the National Institutes of Health (CA53370) to EW and the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Rutgers University, 679 Hoes Lane, Room 140, Piscataway, 08854, NJ, USA

    Ramya Sundararajan & Eileen White

  2. Howard Hughes Medical Institute, NJ, USA

    Guanghua Chen, Chandreyee Mukherjee & Eileen White

  3. Center for Advanced Biotechnology and Medicine, Rutgers University, 679 Hoes Lane, Room 140, Piscataway, 08854, NJ, USA

    Eileen White

  4. Department of Molecular Biology and Biochemistry, Rutgers University, 679 Hoes Lane, Room 140, Piscataway, 08854, NJ, USA

    Eileen White

  5. Cancer Institute of New Jersey, NJ, USA

    Eileen White

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  1. Ramya Sundararajan
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Correspondence to Eileen White.

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Sundararajan, R., Chen, G., Mukherjee, C. et al. Caspase-dependent processing activates the proapoptotic activity of deleted in breast cancer-1 during tumor necrosis factor-alpha-mediated death signaling. Oncogene 24, 4908–4920 (2005). https://doi.org/10.1038/sj.onc.1208681

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