A tumor suppressor function for caspase-2
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
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Creation Date: 2009-03-31 12:00:00
Last Modified: 0001-01-01 12:00:00
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