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Type: Journal article
Title: Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice
Author: Puccini, J.
Shalini, S.
Voss, A.
Gatei, M.
Wilson, C.
Hiwase, D.
Lavin, M.
Dorstyn, L.
Kumar, S.
Citation: Proceedings of the National Academy of Sciences of USA, 2013; 110(49):19920-19925
Publisher: Natl Acad Sciences
Issue Date: 2013
ISSN: 0027-8424
Statement of
Joseph Puccini, Sonia Shalini, Anne K. Voss, Magtouf Gate, Claire H. Wilson, Devendra K. Hiwase, Martin F. Lavin, Loretta Dorstyn and Sharad Kumara
Abstract: Caspase-2, the most evolutionarily conserved member of the caspase family, has been shown to be involved in apoptosis induced by various stimuli. Our recent work indicates that caspase-2 has putative functions in tumor suppression and protection against cellular stress. As such, the loss of caspase-2 enhances lymphomagenesis in Eµ-Myc transgenic mice, and caspase-2 KO (Casp2−/−) mice show characteristics of premature aging. However, the extent and specificity of caspase-2 function in tumor suppression is currently unclear. To further investigate this, ataxia telangiectasia mutated KO (Atm−/−) mice, which develop spontaneous thymic lymphomas, were used to generate Atm−/−Casp2−/− mice. Initial characterization revealed that caspase-2 deficiency enhanced growth retardation and caused synthetic perinatal lethality in Atm−/− mice. A comparison of tumor susceptibility demonstrated that Atm−/−Casp2−/− mice developed tumors with a dramatically increased incidence compared with Atm−/− mice. Atm−/−Casp2−/− tumor cells displayed an increased proliferative capacity and extensive aneuploidy that coincided with elevated oxidative damage. Furthermore, splenic and thymic T cells derived from premalignant Atm−/−Casp2−/− mice also showed increased levels of aneuploidy. These observations suggest that the tumor suppressor activity of caspase-2 is linked to its function in the maintenance of genomic stability and suppression of oxidative damage. Given that ATM and caspase-2 are important components of the DNA damage and antioxidant defense systems, which are essential for the maintenance of genomic stability, these proteins may synergistically function in tumor suppression by regulating these processes.
Keywords: Animals
Mice, Knockout
Genomic Instability
Flow Cytometry
Cytogenetic Analysis
Oxidative Stress
Caspase 2
Kaplan-Meier Estimate
Ataxia Telangiectasia Mutated Proteins
Rights: Copyright status unknown
DOI: 10.1073/pnas.1311947110
Appears in Collections:Aurora harvest 4
Medicine publications

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