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The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis

Nature volume 395, pages 801–804 (1998)Cite this article

Abstract

The development of colonic carcinoma is associated with the mutation of a specific set of genes1. One of these, DCC (deleted in colorectal cancer)2,3,4,5, is a candidate tumour-suppressor gene, and encodes a receptor for netrin-1, a molecule involved in axon guidance6,7,8. Loss of DCC expression in tumours is not restricted to colon carcinoma2, and, although there is no increase in the frequency of tumour formation in DCC hemizygous mice5, re-establishment of DCC expression suppresses tumorigenicity3,4. However, the mechanism of action of DCC is unknown. Here we show that DCC induces apoptosis in the absence of ligand binding, but blocks apoptosis when engaged by netrin-1. Furthermore, DCC is a caspase substrate, and mutation of the site at which caspase-3 cleaves DCC suppresses the pro-apoptotic effect of DCC completely. These results indicate that DCC may function as a tumour-suppressor protein by inducing apoptosis in settings in which ligand is unavailable (for example, during metastasis or tumour growth beyond local blood supply) through functional caspase cascades by a mechanism that requires cleavage of DCC at Asp 1,290.

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Figure 1: DCC expression induces cell death, which is blocked by netrin-1.
Figure 2: Intracellular processing of DCC and DCC-IC are inhibited by netrin-1 and the caspase inhibitor zVAD-fmk.
Figure 3: DCC is a caspase substrate in vitro.
Figure 4: Mutation of the site of cleavage of DCC by caspase-3 suppresses the pro-apoptotic effect of DCC completely.
Figure 5: The dependence domain of DCC lies in the N-terminal portion of the intracellular domain.

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Acknowledgements

We thank B. Vogelstein and E. Fearon for the DCC cDNA, M. Tessier-Lavigne for the netrin-1 cDNA, and F. Martin for the REGb cells. This work was supported in part by grants from the NIH and the VivoRx Corporation.

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Authors and Affiliations

  1. The Burnham Institute, La Jolla, 92037, California, USA

    Patrick Mehlen, Shahrooz Rabizadeh, Scott J. Snipas, Nuria Assa-Munt, Guy S. Salvesen & Dale E. Bredesen

  2. Neuroscience Department, University of California, San Diego, 92093, California, USA

    Patrick Mehlen, Shahrooz Rabizadeh, Scott J. Snipas, Nuria Assa-Munt, Guy S. Salvesen & Dale E. Bredesen

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  1. Patrick Mehlen
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Correspondence to Dale E. Bredesen.

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Mehlen, P., Rabizadeh, S., Snipas, S. et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804 (1998). https://doi.org/10.1038/27441

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