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|Title:||Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability|
|Citation:||Cell Death and Differentiation, 2012; 19(8):1288-1298|
|Publisher:||Nature Publishing Group|
|L Dorstyn, J Puccini, CH Wilson, S Shalini, M Nicola, S Moore and S Kumar|
|Abstract:||Caspase-2 is an initiator caspase, which has been implicated to function in apoptotic and non-apoptotic signalling pathways, including cell-cycle regulation, DNA-damage signalling and tumour suppression. We previously demonstrated that caspase-2 deficiency enhances E1A/Ras oncogene-induced cell transformation and augments lymphomagenesis in the EμMyc mouse model. Caspase-2(-/-) mouse embryonic fibroblasts (casp2(-/-) MEFs) show aberrant cell-cycle checkpoint regulation and a defective apoptotic response following DNA damage. Disruption of cell-cycle checkpoints often leads to genomic instability (GIN), which is a common phenotype of cancer cells and can contribute to cellular transformation. Here we show that caspase-2 deficiency results in increased DNA damage and GIN in proliferating cells. Casp2(-/-) MEFs readily escape senescence in culture and exhibit increased micronuclei formation and sustained DNA damage during cell culture and following γ-irradiation. Metaphase analyses demonstrated that a lack of caspase-2 is associated with increased aneuploidy in both MEFs and in EμMyc lymphoma cells. In addition, casp2(-/-) MEFs and lymphoma cells exhibit significantly decreased telomere length. We also noted that loss of caspase-2 leads to defective p53-mediated signalling and decreased trans-activation of p53 target genes upon DNA damage. Our findings suggest that loss of caspase-2 serves as a key function in maintaining genomic integrity, during cell proliferation and following DNA damage.|
|Keywords:||Cells, Cultured; Fibroblasts; Animals; Mice, Knockout; Humans; Mice; DNA Damage; Disease Models, Animal; Aneuploidy; Genomic Instability; Transfection; Signal Transduction; Cell Growth Processes; Caspase 2; Embryo, Mammalian|
|Rights:||©2012 Macmillan Publishers Limited. All rights reserved.|
|Appears in Collections:||Medicine publications|
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