Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability.
Cell Death Differ
; 19(8): 1288-98, 2012 Aug.
Article
em En
| MEDLINE
| ID: mdl-22498700
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Instabilidade Genômica
/
Caspase 2
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Death Differ
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Austrália