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DAP kinase links the control of apoptosis to metastasis

Nature volume 390, pages 180–184 (1997)Cite this article

Abstract

DAP kinase is a new type of calcium/calmodulin-dependent enzyme that phosphorylates serine/threonine residues on proteins. Its structure contains ankyrin repeats and the ‘death’ domain, and it is associated with the cell cytoskeleton1,2,3. The gene encoding DAP kinase was initially isolated as a positive mediator of apoptosis induced by interferon-γ, by using a strategy of functional cloning4. We have now tested whether this gene has tumour-suppressive activity. We found that lung carcinoma clones, characterized by their highly aggressive metastatic behaviour and originating from two independent murine lung tumours, did not express DAP kinase, in contrast to their low-metastatic counterparts. Restoration of DAP kinase to physiological levels in high-metastatic Lewis carcinoma cells suppressed their ability to form lung metastases after intravenous injection into syngeneic mice, and delayed local tumour growth in a foreign ‘microenvironment’. Conversely, in vivo selection of rare lung lesions following injection into syngeneic mice of low-metastatic Lewis carcinoma cells or of DAP kinase transfectants, was associated with loss of DAP kinase expression. In situ TUNEL staining of tumour sections revealed that DAP kinase expression from the transgene raised the incidence of apoptosis in vivo. DAP-kinase transfectants also showed increased sensitivity in vitro to apoptotic stimuli, of the sort encountered by metastasizing cells at different stages of malignancy. We propose that loss of DAP kinase expression provides a unique mechanism that links suppression of apoptosis to metastasis.

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Figure 1: Immunoblot analysis of DAP kinase expression.
Figure 3: a, In situ TUNEL staining of footpad sections on five days after local injection of 4-cont.
Figure 2: Inverse relationships between DAP kinase expression and metastatic activity.
Figure 4: The growth of the D122 transfectants in semi-solid medium.

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Acknowledgements

We thank E. Feinstein for discussions and for comments on the manuscript, J.L.Kissil, S. Ben-Bassat, D. Popovic and H. El-Shami for technical assistance, and L. M. Franks for the CMT-64 clones. The work was supported by QBI Ltd and by a grant from the Israeli Ministry of Science. A.K. is an Incumbent of the Helena Rubinstein Chair of Cancer Research. L.E. is an Incumbent of the G.F. Duckwitz Chair of Cancer Research.

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Authors and Affiliations

  1. Departments of Molecular Genetics,

    Boaz Inbal, Ofer Cohen & Adi Kimchi

  2. Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Ezra Vadai & Lea Eisenbach

  3. Department of Histopathology, Chaim Sheba Medical Center, Tel-Hashomer, Israel

    Sylvie Polak-Charcon & Juri Kopolovic

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  1. Boaz Inbal
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Correspondence to Adi Kimchi.

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Inbal, B., Cohen, O., Polak-Charcon, S. et al. DAP kinase links the control of apoptosis to metastasis. Nature 390, 180–184 (1997). https://doi.org/10.1038/36599

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