Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice

Puccini, Joseph, Shalini, Sonia, Voss, Anne K., Gatei, Magtouf, Wilson, Claire H., Hiwase, Devendra K., Lavin, Martin F., Dorstyn, Loretta and Kumar, Sharad (2013) Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 110 49: 19920-19925. doi:10.1073/pnas.1311947110


Author Puccini, Joseph
Shalini, Sonia
Voss, Anne K.
Gatei, Magtouf
Wilson, Claire H.
Hiwase, Devendra K.
Lavin, Martin F.
Dorstyn, Loretta
Kumar, Sharad
Title Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice
Formatted title
Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2013-12-03
Sub-type Article (original research)
DOI 10.1073/pnas.1311947110
Volume 110
Issue 49
Start page 19920
End page 19925
Total pages 6
Editor Vishva M. Dixit
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted 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.

Significance The cysteine protease caspase-2 has been implicated in the suppression of oncogene-mediated tumor formation. However, the mechanisms underlying the function of caspase-2 as a tumor suppressor are not well defined. In this study, we use a well-characterized mouse lymphoma model and demonstrate a critical role for caspase-2 in maintaining genome stability and in the suppression of tumorigenesis following loss of the essential DNA repair gene ataxia telangiectasia mutated (Atm). Our findings suggest that caspase-2 cooperates with ATM to suppress genomic instability, oxidative stress, and tumor progression.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2014 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 23 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 16 Dec 2013, 20:56:57 EST by Roheen Gill on behalf of UQ Centre for Clinical Research