Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice

Shalini, Sonia; Dorstyn, Loretta; Wilson, Christopher M.; Puccini, Joseph; Ho, Lien H.; Kumar, Sharad

doi:10.1038/cdd.2012.13

Cited by 74 publications

(108 citation statements)

References 34 publications

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“…Histological analysis of livers from young (6-9 weeks) non-DEN-injected tumour free Casp2 −/− mice had no abnormal liver morphology or perturbed hepatocyte nuclei. However, consistent with previous findings 23 by 10 months of age all PBS-injected Casp2 −/− mice displayed an increase in nuclear volume (karyomegaly) and binucleation ( Supplementary Figure 1a and b).…”

Section: Resultssupporting

confidence: 92%

“…21,22 Caspase-2 deficiency in mice results in metabolic perturbations and aged caspase-2 mice show increased oxidative stress and DNA damage. 5,21,23 DEN-induced tumour formation involves the generation of DNA adducts, 10 and human HCC is commonly associated with genomic instability. 24 These observations, combined with the known tumour suppressor role in lymphoma and MMTV-driven mammary carcinoma, suggest a possible role of caspase-2 in HCC.…”

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Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

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Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damageinduced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2 −/− ) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2 −/− mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2 −/− mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis. The initiator caspase, caspase-2, has recently emerged as a tumour suppressor with loss of this protein being associated with increased lymphomagenesis in ATM-deficient mice and Eμ-Myc transgenic mice, and MMTV/c-neu-driven mammary carcinoma. 1-4 Caspase-2 has been shown to protect cells from oxidative stress, DNA damage and genomic instability, and caspase-2 deficiency is linked to chromosomal instability and aneuploidy. 1,5,6 However, currently little is known about the possible role of caspase-2 in carcinogenesis induced by ROS and DNA damage.Hepatocellular carcinoma (HCC) is among the most common cancers and is the second leading cause of cancer-related deaths worldwide. 7 Development of HCC is multifaceted progressing from DNA damage to dysplasia, adenoma development and malignant transformation of hepatocytes. 7,8 The major risk factors of HCC include viral hepatitis, excessive alcohol consumption, carcinogens and metabolic diseases. 7,8 Despite this, the molecular causes of the disease are relatively less understood. Diethylnitrosamine (DEN) is a DNA alkylating and ROS inducing carcinogen that is widely used as a model to study the progression of HCC in rodents. 9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. 7-10 It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC. 11-13 While loss of apoptosis would indirectly favour proliferation, this is not universa...

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Section: Resultssupporting

confidence: 92%

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confidence: 99%

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

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“…20 Also, Casp2 À / À mice show signs of premature ageing and metabolic and oxidative stress and are noticeably leaner as they age. 21,22 Overall, Casp2 À / À mice have provided only limited insight into the physiological functions of this enigmatic caspase. As stated above, compensatory mechanisms have been proposed to account for this lack of an overt phenotype.…”

Section: Caspase-2 Knockout Micementioning

confidence: 99%

“…Contrary to this prediction, caspase-2 deletion is not sufficient to induce spontaneous tumorigenesis in mice. 21 However, when crossed into an oncogenic background, the function of caspase-2 in tumorigenesis becomes apparent. Deletion of caspase-2 in Em-Myc transgenic mice accelerates lymphomagenesis, providing the first direct line of evidence for a tumour suppressor function for caspase-2.…”

Section: Caspase-2 As a Tumour Suppressor -Evidence From Mouse Modelsmentioning

confidence: 99%

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Caspase-2 as a tumour suppressor

2013

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Ever since its discovery 20 years ago, caspase-2 has been enigmatic and its function somewhat controversial. Although many in vitro studies suggested that caspase-2 was important for apoptosis, demonstrating an in vivo cell death role for this caspase has been more problematic, with caspase-2-deficient mice showing limited, tissue-specific cell death defects. Recent results from different laboratories suggest that at least one of its physiological roles in animals is to protect against cellular stress and transformation. As such, loss of caspase-2 augments tumorigenesis in some mouse models of cancer, assigning a tumour suppressor function to this enigmatic caspase. This review focuses on this seemingly non-apoptotic function of caspase-2 as a tumour suppressor and reconciles some of the recent findings in the field.

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Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly

Harel

Hacohen

Shaag

et al. 2017

American J of Med Genetics Pt A

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Lissencephaly is a severe malformation of cortical development, most often attributed to abnormalities in neuronal migration. It is associated with a severe prognosis including developmental delay, intellectual disability, and seizures. Lissencephaly can be reliably diagnosed during late gestation by neurosonography or fetal magnetic resonance imaging (MRI). We report two sibling male fetuses who were diagnosed with delayed cortical sulcation highly suggestive of lissencephaly during late pregnancy. After receiving genetic counseling, the parents elected to terminate the pregnancies based on the neuroradiological findings and the associated severe prognosis. Whole exome sequencing (WES) of an affected fetus, and subsequent Sanger sequencing of the second fetus, revealed a homozygous frameshift variant in CRADD, which encodes an adaptor protein that interacts with PIDD and caspase-2 to initiate apoptosis. Biallelic variants in this gene have been recently reported to cause "thin" lissencephaly and intellectual disability. Interestingly, the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation by brain MRI which revealed hypogyration. This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges of prenatal genetic counseling.

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Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice

Cited by 74 publications

References 34 publications

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Caspase-2 as a tumour suppressor

Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly

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