title: A tumor suppressor function for caspase-2.
abstract: 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 Emu-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 gamma-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.
authors.affiliation: Centre for Cancer Biology, Hanson Institute, Frome Road, Adelaide, SA 5000, Australia.
authors.forename: Lien Ha
authors.initials: LH
authors.lastname: Ho
authors.forename: Robyn
authors.initials: R
authors.lastname: Taylor
authors.forename: Loretta
authors.initials: L
authors.lastname: Dorstyn
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Cakouros
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000818:Animals; D017209:Apoptosis; D053143:Caspase 2 / Q000172:deficiency* / Q000502:physiology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D025521:Tumor Suppressor Proteins
chemical_list: D025521:Tumor Suppressor Proteins; C090208:Casp2 protein, mouse; D053143:Caspase 2