tumor suppressor function for caspase-2

Apoptosis is mediated by the caspase family of proteases that act as effectors of cell death by cleaving many cellular substrates. Caspase-2 is one of the most evolutionarily conserved caspases, yet its physiological function has remained enigmatic because caspase-2-deficient mice develop normally a...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-03, Vol.106 (13), p.5336-5341
Main Authors: Ho, Lien Ha, Taylor, Robyn, Dorstyn, Loretta, Cakouros, Dimitrios, Bouillet, Philippe, Kumar, Sharad
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biochemistry
Biological Sciences
Blood
Caspase 2 - deficiency
Caspase 2 - physiology
Cell cycle
Cell death
Cell growth
Cell Proliferation
Cell Transformation, Neoplastic
Cells
Cells, Cultured
Disease Models, Animal
DNA damage
Genotypes
Lymphoma
Lymphoma - etiology
Mice
Mice, Knockout
Mice, Nude
Proteases
Proteins
Rodents
Tumor Suppressor Proteins
Tumors
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Summary:Apoptosis is mediated by the caspase family of proteases that act as effectors of cell death by cleaving many cellular substrates. Caspase-2 is one of the most evolutionarily conserved caspases, yet its physiological function has remained enigmatic because caspase-2-deficient mice develop normally and are viable. We report here that the caspase-2⁻/⁻ mouse embryonic fibroblasts (MEFs) show increased proliferation. When transformed with E1A and Ras oncogenes, caspase-2⁻/⁻ MEFs grew significantly faster than caspase-2⁺/⁺ MEFs and formed more aggressive and accelerated tumors in nude mice. To assess whether the loss of caspase-2 predisposes animals to tumor development, we used the mouse Eμ-Myc lymphoma model. Our findings suggest that loss of even a single allele of caspase-2 resulted in accelerated tumorigenesis, and this was further enhanced in caspase-2⁻/⁻ mice. The caspase-2⁻/⁻ cells showed resistance to apoptosis induced by chemotherapeutic drugs and DNA damage. Furthermore, caspase-2⁻/⁻ MEFs had a defective apoptotic response to cell-cycle checkpoint regulation and showed abnormal cycling following γ-irradiation. These data show that loss of caspase-2 results in an increased ability of cells to acquire a transformed phenotype and become malignant, indicating that caspase-2 is a tumor suppressor protein.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0811928106