A tumor suppressor function for caspase-2

Ho, LH; Taylor, R; Dorstyn, L; Cakouros, D; Bouillet, P; Kumar, S

Author(s): Ho, LH; Taylor, R; Dorstyn, L; Cakouros, D; Bouillet, P; Kumar, S;
Details: Publication Year 2009-03-31,Volume 106,Issue #13,Page 5336-5341
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
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 E mu-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.
Publisher: NATL ACAD SCIENCES
Keywords: ACUTE LYMPHOBLASTIC-LEUKEMIA; PROGRAMMED CELL-DEATH; NUCLEAR-LOCALIZATION; PROTEIN-LEVELS; APOPTOSIS; MOUSE; BCL-2; BIM; P53; ACTIVATION
Publisher's Version: https://doi.org/10.1073/pnas.0811928106
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-03-31 12:00:00