The p53-caspase-2 axis in the cell cycle and DNA damage response

Caspase-2 was discovered almost three decades ago. It was one of the first two mammalian homologs of CED-3, the other being interleukin 1β-converting enzyme (ICE/caspase-1). Despite high similarity with CED-3 and its fly and mammalian counterparts (DRONC and caspase-9, respectively), the function of caspase-2 in apoptosis has remained enigmatic. A number of recent studies suggest that caspase-2 plays an important role in the regulation of p53 in response to cellular stress and DNA damage to prevent the proliferation and accumulation of damaged or aberrant cells. Here, we review these recent observations and their implications in caspase-2-mediated cellular death, senescence, and tumor suppression.Yoon Lim, Loretta Dorstyn and Sharad Kuma

Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice

The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2−/− mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo.Swati Dawar, Nur Hezrin Shahrin, Nikolina Sladojevic, Richard J D, Andrea, Loretta Dorstyn, Devendra K Hiwase and Sharad Kuma

Belonging in the Online World: Older Adults' Use of Internet for Community

Objective: To explore older Australians’ experiences of using computermediated communication (CMC) to engage with their social networks and communities. Background: Use of CMC among older adults has been associated with favourable social outcomes. How older adults engage with others to foster these outcomes is less well known. Understanding this may be useful when developing programs to encourage older adults’ use of CMC for social purposes. Methods: In-depth semi-structured interviews with 12 adults (five women, seven men; aged 69 to 81) were conducted. Interview questions focused on individuals’ use of CMC to engage with online communities. Data were transcribed and thematically analysed. Results: Two overarching themes relating to a sense of Belonging and Support emerged. Belonging was most heavily emphasised, and included subthemes on how participants experienced their close social networks online, as well as their broader engagement with building interests and identity. Support arose to a lesser extent, and included subthemes relating to how CMC was used not only for the provision and receipt of such, but also to signal availability or need for support. Throughout, participants consistently weighed the benefits of CMC against the disadvantages. Conclusion: The findings highlight the importance of social networks and online communities for older adults and, in particular, how CMC facilitates feelings of belongingness and provides opportunities for reciprocal instrumental, emotional, and informational support. Future research needs to consider the importance of having a sense of belonging when describing the social functioning of digitally literate older adults.Belinda Grace Fuss, Diana Dorstyn, Lynn War

Mindfulness Therapies for Improving Mental Health in Parents of Children with a Developmental Disability: a Systematic Review

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Mindfulness offers promise as a therapy approach for parents of children with developmental disabilities (DD), however its effectiveness in managing mental health symptoms remains unclear. This review quantitatively examines the comparative effectiveness of mindfulness-based and informed interventions, drawing on the evidence base from randomised controlled trials (RCTs). Eight RCTs were identified from the Embase, PsycINFO, PubMed and Scopus databases. Risk of bias was assessed using the Cochrane Collaboration tool and Hedges’ g effect sizes, with associated 95% confidence intervals and p values calculated. Parents who completed Mindful Parenting or Mindfulness-Based Stress Reduction programs reported immediate and large to very large reductions in psychological distress (gw range:.39–1.94), with some improvements maintained up to 6 months post-treatment. A single study reported short-term benefits with Acceptance and Commitment Therapy. Evidence for the mental health benefits of mindfulness for parents of children with DD is still at an early stage. Controlled trials are needed to determine the differential effects of specific mindfulness techniques and how to best adapt this approach to best meet the unique needs of a vulnerable caregiver population

Caspase-2 deficiency enhances whole-body carbohydrate utilisation and prevents high-fat diet-induced obesity

Published online 26 October 2017Caspase-2 has been shown to be involved in metabolic homeostasis. Here, we show that caspase-2 deficiency alters basal energy metabolism by shifting the balance in fuel choice from fatty acid to carbohydrate usage. At 4 weeks of age, whole-body carbohydrate utilisation was increased in Casp2-/- mice and was maintained into adulthood. By 17 weeks of age, Casp2-/- mice had reduced white adipose mass, smaller white adipocytes decreased fasting blood glucose and plasma triglycerides but maintained normal insulin levels. When placed on a 12-week high-fat diet (HFD), Casp2-/- mice resisted the development of obesity, fatty liver, hyperinsulinemia and insulin resistance. In addition, HFD-fed Casp2-/- mice had reduced white adipocyte hypertrophy, apoptosis and expansion of both subcutaneous and visceral adipose depots. Increased expression of UCP1 and the maintenance of adiponectin levels in white adipose tissue of HFD-fed Casp2-/- mice indicated increased browning and adipocyte hyperplasia. We found that while the preference for whole-body carbohydrate utilisation was maintained, HFD-fed Casp2-/- mice were not impaired in their ability to switch to utilising fats as a fuel source. Our findings suggest that caspase-2 impacts basal energy metabolism by regulating adipocyte biology and fat expansion, most likely via a non-apoptotic function. Furthermore, we show that caspase-2 deficiency shifts the balance in fuel choice towards increased carbohydrate utilisation and propose that this is due to mild energy stress. As a consequence, Casp2-/- mice show an adaptive remodelling of adipose tissue that protects from HFD-induced obesity and improves glucose homeostasis while paradoxically increasing their susceptibility to oxidative stress induced damage and premature ageing.Claire H Wilson, Andrej Nikolic, Stephen J Kentish, Marianne Keller, George Hatzinikolas, Loretta Dorstyn, Amanda J Page and Sharad Kuma

p53 accumulation following cytokinesis failure in the absence of caspase-2

Abstract not availableYoon Lim, Dylan De Bellis, Loretta Dorstyn, Sharad Kuma

An unexpected role for caspase-2 in neuroblastoma

Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene-mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the Eμ-Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH-MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2(-/-) mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2(+/+) counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2(-/-) tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis.L Dorstyn, J Puccini, A Nikolic, S Shalini, CH Wilson, MD Norris, M Haber and S Kuma

Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice

Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2 (-/-) ) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2 (-/-) mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18-22 months) male Casp2 (-/-) mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2 (-/-) mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2 (-/-) mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2 (-/-) mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.CH Wilson, A Nikolic, SJ Kentish, S Shalini, G Hatzinikolas, AJ Page, L Dorstyn and S Kuma

Caspase-2-mediated cell death is required for deleting aneuploid cells

Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2-/-) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2-/- mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.S Dawar, Y Lim, J Puccini, M White, P Thomas, L Bouchier-Hayes, D R Green, L Dorstyn and S Kuma

Age-related proteostasis and metabolic alterations in Caspase-2-deficient mice

Ageing is a complex biological process for which underlying biochemical changes are still largely unknown. We performed comparative profiling of the cellular proteome and metabolome to understand the molecular basis of ageing in Caspase-2-deficient (Casp2−/−) mice that are a model of premature ageing in the absence of overt disease. Age-related changes were determined in the liver and serum of young (6–9 week) and aged (18–24 month) wild-type and Casp2−/− mice. We identified perturbed metabolic pathways, decreased levels of ribosomal and respiratory complex proteins and altered mitochondrial function that contribute to premature ageing in the Casp2−/− mice. We show that the metabolic profile changes in the young Casp2−/− mice resemble those found in aged wild-type mice. Intriguingly, aged Casp2−/− mice were found to have reduced blood glucose and improved glucose tolerance. These results demonstrate an important role for caspase-2 in regulating proteome and metabolome remodelling during ageing.CH Wilson, S Shalini, A Filipovska, TR Richman, S Davies, SD Martin, SL McGee, J Puccini, A Nikolic, L Dorstyn, and S Kuma