| Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability. | |
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MedLine Citation:
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PMID: 22498700 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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L Dorstyn; J Puccini; C H Wilson; S Shalini; M Nicola; S Moore; S Kumar |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-04-13 |
Journal Detail:
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Title: Cell death and differentiation Volume: 19 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-07-09 Completed Date: 2013-01-18 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 1288-98 Citation Subset: IM |
Affiliation:
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Department of Haematology, Centre for Cancer Biology/SA Pathology, Adelaide, SA, Australia. Loretta.Dorstyn@health.sa.gov.au |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aneuploidy Animals Caspase 2 / deficiency*, genetics, metabolism Cell Growth Processes / genetics Cells, Cultured DNA Damage* Disease Models, Animal Embryo, Mammalian / cytology Fibroblasts / cytology, physiology Genomic Instability* Humans Mice Mice, Knockout Signal Transduction Transfection |
| Chemical | |
Reg. No./Substance:
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EC 3.4.22.-/Caspase 2 |
| Comments/Corrections | |
Erratum In:
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Cell Death Differ. 2012 Aug;19(8):1411 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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