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

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.

• Authors: Joseph Puccini, Sonia Shalini, Anne K Voss, Magtouf Gatei, Claire H Wilson, Devendra K Hiwase, Martin F Lavin, Loretta Dorstyn, Sharad Kumar
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 49 Pg. 19920-5 (Dec 03 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 24248351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ataxia Telangiectasia Mutated Proteins
• Caspase 2

Topics

• Animals
• Ataxia Telangiectasia Mutated Proteins (deficiency, metabolism)
• Caspase 2 (deficiency, metabolism)
• Cytogenetic Analysis
• Flow Cytometry
• Genomic Instability (genetics, physiology)
• Immunohistochemistry
• Kaplan-Meier Estimate
• Lymphoma (metabolism, physiopathology)
• Mice
• Mice, Knockout
• Oxidative Stress (genetics)