Abstract
Despite being the most evolutionarily conserved of the mammalian caspases, little is understood about the cellular function of caspase-2 in normal tissues or what role caspase-2 may have in the progression of human disease. It has been reported that deletion of the caspase-2 gene (Casp2), accelerates Eμ-myc lymphomagenesis in mice, and thus caspase-2 may act as a tumor suppressor in hematological malignancies. Here, we sought to extend these findings to epithelial cancers by examining the potential role of caspase-2 as a tumor suppressor in the mouse mammary carcinogenesis model; MMTV/c-neu. The rate of tumor acquisition was significantly higher in multiparous Casp2−/−/MMTV mice compared with Casp2+/+/MMTV and Casp2+/−/MMTV mice. Cells from Casp2−/−/MMTV tumors were often multinucleated and displayed bizarre mitoses and karyomegaly, while cells from Casp2+/+/MMTV and Casp2+/−/MMTV tumors never displayed this phenotype. Tumors from Casp2−/−/MMTV animals had a significantly higher mitotic index than tumors from Casp2+/+/MMTV and Casp2+/−/MMTV animals. Cell cycle analysis of Casp2−/− E1A/Ras-transformed mouse embryonic fibroblasts (MEF) also indicated a higher proliferative rate in the absence of caspase-2. In vitro assays further illustrated that MEF had increased genomic instability in the absence of caspase-2. This appears to be due to disruption of the p53 pathway because we observed a concomitant decrease in the induction of the p53 target genes, Pidd, p21 and Mdm2. Thus caspase-2 may function as a tumor suppressor, in part, through regulation of cell division and genomic stability.
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Abbreviations
- 5-FU:
-
5-Fluorouracil
- ALL:
-
acute lymphoblastic leukemia
- AML:
-
acute myeloid leukemia
- ATM:
-
ataxia telangiectasia mutated
- ATR:
-
ataxia telangiectasia and Rad3-related protein
- CAD:
-
carbamyl phosphate synthetase/aspartate transcarbamylase/dihydro-orotase
- Chk1:
-
checkpoint kinase 1
- MDM2:
-
mammalian double minute 2
- MEF:
-
mouse embryonic fibroblasts
- MMTV:
-
mouse mammary tumor virus
- MN:
-
multinucleated
- PALA:
-
N-(phosphonoacetyl)-L-aspartate
- PIDD:
-
p53-induced protein with a death domain
- shRNA:
-
short hairpin RNA
- T-ALL:
-
T cell acute lymphoblastic leukemia
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Acknowledgements
This work was supported by the National Institutes of Health AI47891 (DRG) and 5F32CA1360912 (MJP). We thank An Lu for technical help and Jonathan Flanagan for helpful discussions.
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Parsons, M., McCormick, L., Janke, L. et al. Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice. Cell Death Differ 20, 1174–1182 (2013). https://doi.org/10.1038/cdd.2013.38
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DOI: https://doi.org/10.1038/cdd.2013.38
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