Cell death
Apoptosis
caspase biology
Tumour suppression
Genomic instability
51
Scopus Publications
Scopus Publications
Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice Loretta Dorstyn, Yoon Lim, Jack Scanlan, Emma McLennan, Dylan De Bellis, Michael Katschner, John Finnie, Samantha Emery-Corbin, Jumana Yousef, Laura F. Dagley, Chung H. Kok, Sonia S. Shah, Chiaki Takahashi, Mark A. Febbraio, Sharad Kumar Science Advances, 2026 Hepatocyte polyploidization promotes liver homeostasis by enhancing resistance to cellular stress. Caspase-2, a proapoptotic protease, restricts polyploidization by deleting polyploid and aneuploid cells. While caspase-2 protects against diet-induced hepatic injury, it also acts as a tumor suppressor by controlling genomic instability and oxidative stress. To investigate these roles, we assessed hepatic ploidy dynamics, liver damage, and age-associated tumorigenesis in caspase-2–deficient and catalytically inactive mutant mice. We found that caspase-2 loss promotes early-onset hepatocyte hyperpolyploidy, accompanied by progressive liver inflammation, fibrosis, oxidative liver damage, ferroptosis, and higher incidence of spontaneous hepatocellular carcinoma in aged animals. Proteomic profiling revealed a pathogenic polyploidy–associated signature associated with caspase-2 deficiency and increased predisposition to liver disease and malignancy. These findings establish caspase-2 enzymatic activity as a critical regulator of hepatic genome stability and preventing age-related liver cancer that strongly argue against therapeutic caspase-2 inhibition as a strategy for managing liver injury or cancer risk.
Understanding Developmental Cell Death Using Drosophila as a Model System Ruchi Umargamwala, Jantina Manning, Loretta Dorstyn, Donna Denton, Sharad Kumar Cells, 2024 Cell death plays an essential function in organismal development, wellbeing, and ageing. Many types of cell deaths have been described in the past 30 years. Among these, apoptosis remains the most conserved type of cell death in metazoans and the most common mechanism for deleting unwanted cells. Other types of cell deaths that often play roles in specific contexts or upon pathological insults can be classed under variant forms of cell death and programmed necrosis. Studies in Drosophila have contributed significantly to the understanding and regulation of apoptosis pathways. In addition to this, Drosophila has also served as an essential model to study the genetic basis of autophagy-dependent cell death (ADCD) and other relatively rare types of context-dependent cell deaths. Here, we summarise what is known about apoptosis, ADCD, and other context-specific variant cell death pathways in Drosophila, with a focus on developmental cell death.
The role of caspases as executioners of apoptosis Sharad Kumar, Loretta Dorstyn, Yoon Lim Biochemical Society Transactions, 2022 Caspases are a family of cysteine aspartyl proteases mostly involved in the execution of apoptotic cell death and in regulating inflammation. This article focuses primarily on the evolutionarily conserved function of caspases in apoptosis. We summarise which caspases are involved in apoptosis, how they are activated and regulated, and what substrates they target for cleavage to orchestrate programmed cell death by apoptosis.
The p53-caspase-2 axis in the cell cycle and DNA damage response Yoon Lim, Loretta Dorstyn, Sharad Kumar Experimental and Molecular Medicine, 2021 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.
Phosphorylation by Aurora B kinase regulates caspase-2 activity and function Yoon Lim, Dylan De Bellis, Jarrod J. Sandow, Luisa Capalbo, Pier Paolo D’Avino, James M. Murphy, Andrew I. Webb, Loretta Dorstyn, Sharad Kumar Cell Death and Differentiation, 2021 Mitotic catastrophe (MC) is an important oncosuppressive mechanism that serves to eliminate cells that become polyploid or aneuploid due to aberrant mitosis. Previous studies have demonstrated that the activation and catalytic function of caspase-2 are key steps in MC to trigger apoptosis and/or cell cycle arrest of mitotically defective cells. However, the molecular mechanisms that regulate caspase-2 activation and its function are unclear. Here, we identify six new phosphorylation sites in caspase-2 and show that a key mitotic kinase, Aurora B kinase (AURKB), phosphorylates caspase-2 at the highly conserved residue S384. We demonstrate that phosphorylation at S384 blocks caspase-2 catalytic activity and apoptosis function in response to mitotic insults, without affecting caspase-2 dimerisation. Moreover, molecular modelling suggests that phosphorylation at S384 may affect substrate binding by caspase-2. We propose that caspase-2 S384 phosphorylation by AURKB is a key mechanism that controls caspase-2 activation during mitosis.
Transcriptome profiling of caspase-2 deficient EμMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling Loretta Dorstyn, Emily Hackett-Jones, Andrej Nikolic, Murray D. Norris, Yoon Lim, John Toubia, Michelle Haber, Sharad Kumar Cell Death and Disease, 2019 Abstract Caspase-2 is a highly conserved cysteine protease with roles in apoptosis and tumor suppression. Our recent findings have also demonstrated that the tumor suppression function of caspase-2 is context specific. In particular, while caspase-2 deficiency augments lymphoma development in the EμMyc mouse model, it leads to delayed neuroblastoma development in Th-MYCN mice. However, it is unclear how caspase-2 mediates these differential outcomes. Here we utilized RNA sequencing to define the transcriptomic changes caused by caspase-2 ( Casp2 −/− ) deficiency in tumors from EμMyc and Th-MYCN mice. We describe key changes in both lymphoma and neuroblastoma-associated genes and identified differential expression of the EGF-like domain-containing gene, Megf6 , in the two tumor types that may contribute to tumor outcome following loss of Casp2 . We identified a panel of genes with altered expression in Th-MYCN/Casp2 −/− tumors that are strongly associated with neuroblastoma outcome, with roles in melanogenesis, Wnt and Hippo pathway signaling, that also contribute to neuronal differentiation. In contrast, we found that key changes in gene expression in the EμMyc/Casp2 −/− tumors, are associated with increased immune signaling and T-cell infiltration previously associated with more aggressive lymphoma progression. In addition, Rap1 signaling pathway was uniquely enriched in Casp2 deficient EμMyc tumors. Our findings suggest that Casp2 deficiency augments immune signaling pathways that may be in turn, enhance lymphomagenesis. Overall, our study has identified new genes and pathways that contribute to the caspase-2 tumor suppressor function and highlight distinct roles for caspase-2 in different tissues.
Caspase-2 deficiency enhances whole-body carbohydrate utilisation and prevents high-fat diet-induced obesity Claire H Wilson, Andrej Nikolic, Stephen J Kentish, Marianne Keller, George Hatzinikolas, Loretta Dorstyn, Amanda J Page, Sharad Kumar Cell Death and Disease, 2017 Abstract Caspase-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.
A tumor suppressor function for caspase-2 Lien Ha Ho, Robyn Taylor, Loretta Dorstyn, Dimitrios Cakouros, Philippe Bouillet, Sharad Kumar Proceedings of the National Academy of Sciences of the United States of America, 2009
Characterization of the Drosophila Caspase, DAMM Natasha L. Harvey, Tasman Daish, Kathryn Mills, Loretta Dorstyn, Leonie M. Quinn, Stuart H. Read, Helena Richardson, Sharad Kumar Journal of Biological Chemistry, 2001
DRONC, an ecdysone-inducible Drosophila caspase Loretta Dorstyn, Paul A. Colussi, Leonie M. Quinn, Helena Richardson, Sharad Kumar Proceedings of the National Academy of Sciences of the United States of America, 1999
Caspases in cell death. Loretta Dorstyn, Makoto Kinoshita, Sharad Kumar Results and Problems in Cell Differentiation, 1998
