DAP kinase links the control of apoptosis to metastasis

Boaz Inbal, Ofer Cohen, Sylvie Polak-Charcon, Juri Kopolovic, Ezra Vadai, Lea Eisenbach and Adi Kimchi ()
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Boaz Inbal: Departments of Molecular Genetics
Ofer Cohen: Departments of Molecular Genetics
Sylvie Polak-Charcon: Chaim Sheba Medical Center
Juri Kopolovic: Chaim Sheba Medical Center
Ezra Vadai: Immunology, Weizmann Institute of Science
Lea Eisenbach: Immunology, Weizmann Institute of Science
Adi Kimchi: Departments of Molecular Genetics

Nature, 1997, vol. 390, issue 6656, 180-184

Abstract: 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.

Date: 1997
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DOI: 10.1038/36599

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