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Papers by John Abrams

Cell Death & Differentiation

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. ... more Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

Genes & Development, 2020

p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated... more p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5′UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that co...

Development, 1993

The deliberate and orderly removal of cells by programmed cell death is a common phenomenon durin... more The deliberate and orderly removal of cells by programmed cell death is a common phenomenon during the development of metazoan animals. We have examined the distribution and ultrastructural appearance of cell deaths that occur during embryogenesis in Drosophila melanogaster. A large number of cells die during embryonic development in Drosophila. These cells display ultrastructural features that resemble apoptosis observed in vertebrate systems, including nuclear condensation, fragmentation and engulfment by macrophages. Programmed cell deaths can be rapidly and reliably visualized in living wild-type and mutant Drosophila embryos using the vital dyes acridine orange or nile blue. Acridine orange appears to selectively stain apoptotic forms of death in these preparations, since cells undergoing necrotic deaths were not significantly labelled. Likewise, toluidine blue staining of fixed tissues resulted in highly specific labelling of apoptotic cells, indicating that apoptosis leads to...

Cell death and differentiation, Jan 23, 2018

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines f... more Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The miss...

The Journal of Cell Biology, 2000

Mechanisms of Development, 2015

Elimination of cells and tissues by apoptosis is a highly conserved and tightly regulated process... more Elimination of cells and tissues by apoptosis is a highly conserved and tightly regulated process. In Drosophila, the entire wing epithelium is completely removed shortly after eclosion. The cells that make up this epithelium are collectively eliminated through a highly synchronized form of apoptotic cell death, involving canonical apoptosome genes. Here we present evidence that collective cell death does not require cell-cell contact and show that transcription of the IAP antagonist, head involution defective (Abdelwahid, Yokokura et al.), is acutely induced in wing epithelial cells prior to this process. hid mRNAs accumulate to levels that exceed a component of the ribosome and likewise, Hid protein becomes highly abundant in these same cells. hid function is required for collective cell death, since loss of function mutants show persisting wing epithelial cells and, furthermore, silencing of the hormone bursicon in the CNS produced collective cell death defective phenotypes manifested in the wing epithelium. Taken together, our observations suggest that acute induction of Hid primes wing epithelial cells for collective cell death and that Bursicon is a strong candidate to trigger this process, possibly by activating the abundant pool of Hid protein already present.

Oncogene, Jan 12, 2004

The central components of the execution phase of apoptosis in worms, flies, and humans are member... more The central components of the execution phase of apoptosis in worms, flies, and humans are members of the caspase protease family. Work in Drosophila and mammalian systems has revealed a web of interactions that govern the activity of these proteases, and two fundamental control points have been identified. These are zymogen activation - the process that converts a latent caspase into its active form, and inhibition of the resulting active protease. In humans, the driving force for caspase activity is activation of the zymogens, but in Drosophila, a major thrust is derepression of caspase inhibitors. In this review, we consider evidence for these two distinct events in terms of the regulation of caspase activity. This sets the scene for therapy to reinstate the normal death mechanisms that have been overcome in a cancer cell's quest for immortality.

IET Image Processing, 2015

Apoptotic programmed cell death (PCD) is a fundamental aspect of developmental maturation. Howeve... more Apoptotic programmed cell death (PCD) is a fundamental aspect of developmental maturation. However, the authors' understanding of apoptosis, especially in the multi-cell regime, is incomplete because of the difficulty of identifying dying cells by conventional strategies. Realtime in vivo microscopy of Drosophila, an excellent model system for studying the PCD during development, has been used to uncover plausible collective apoptosis at the tissue level, although the dynamic regulation of the process remains to be deciphered. In this work, the authors have developed an image-analysis program that can quantitatively analyse time-lapse microscopy of live tissues undergoing apoptosis with a fluorescent nuclear marker, and subsequently extract the spatiotemporal patterns of multicellular response. The program can process a large number of cells (>10 3) automatically tracked across sets of image frames. It is applied to characterise the apoptosis of Drosophila wing epithelium at eclosion. Using the natural anatomic structures as reference, the authors identify dynamic patterns in the progression of PCD within the Drosophila tissues. The results not only confirm the previously observed collective multi-cell behaviour from a quantitative perspective, but also reveal a plausible role played by the anatomic structures, such as the wing veins, in the PCD propagation across the Drosophila wing.

Cell death and differentiation, 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, a... more Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exe...

The Journal of Cell Biology, 1999

Drosophila affords a genetically well-defined system to study apoptosis in vivo. It offers a powe... more Drosophila affords a genetically well-defined system to study apoptosis in vivo. It offers a powerful extension to in vitro models that have implicated a requirement for cytochrome c in caspase activation and apoptosis. We found that an overt alteration in cytochrome c anticipates programmed cell death (PCD) in Drosophila tissues, occurring at a time that considerably precedes other known indicators of apoptosis. The altered configuration is manifested by display of an otherwise hidden epitope and occurs without release of the protein into the cytosol. Conditional expression of the Drosophila death activators, reaper or grim, provoked apoptogenic cytochrome c display and, surprisingly, caspase activity was necessary and sufficient to induce this alteration. In cell-free studies, cytosolic caspase activation was triggered by mitochondria from apoptotic cells but identical preparations from healthy cells were inactive. Our observations provide compelling validation of an early role fo...

Oncogene, 2003

In mammals, members of the tumor necrosis factor (TNF) family play an important role in the regul... more In mammals, members of the tumor necrosis factor (TNF) family play an important role in the regulation of cellular proliferation, differentiation and programmed cell death. We describe isolation and characterization of an orthologous ligand/receptor axis in Drosophila. The ligand, designated Eiger, is a type II membrane glycosylated protein, which can be cleaved at residue 145 and released from the cell surface as a soluble factor, thereby representing the first potential cytokine to be described in Drosophila. Eiger exists in two alternatively spliced isoforms, Eiger long (Eiger-L) and Eiger short (Eiger-s), both of which are expressed throughout development and in the adult. We also describe the isolation and characterization of a novel Drosophila member of the TNF receptor family, designated Wengen, which is a type I membrane protein that can physically interact with the recently described TRAF2 homolog dTRAF2. Both Eiger and Wengen are expressed in distinctive patterns during embryogenesis and Eiger is responsive to genotoxic stress. Forced expression of Eiger-L, Eiger-s or Wengen, caused apoptotic cell death which could be rescued by caspase inhibitors or the JNK phosphatase Puckered. In addition, Eiger-induced cell killing was attenuated by RNAi-mediated suppression of Wengen. Our results illustrate that Eiger and Wengen represent proximal components of an evolutionarily conserved TNF-like signaling pathway in Drosophila.

Journal of Biological Chemistry, 1996

REAPER (RPR) is a 65-amino acid protein that is critical activator of programmed cell death in Dr... more REAPER (RPR) is a 65-amino acid protein that is critical activator of programmed cell death in Drosophila. On the basis of sequence alignment data, it was recently proposed that RPR might represent an ancestral molecule from which the death domain in a number of proteins may have evolved. We tested this idea by examining the activity of mutations in RPR that parallel inactivation mutations of the tumor necrosis factor receptor 1 death domain. The RPR mutants retained potent apoptotic function, suggesting that cell death activity mediated by RPR is distinct from signaling by the tumor necrosis factor receptor 1 death domain.

Journal of Biological Chemistry, 2000

Dronc is a caspase recruitment domain-containing Drosophila caspase that is expressed in a tempor... more Dronc is a caspase recruitment domain-containing Drosophila caspase that is expressed in a temporally and spatially restricted fashion during development. Dronc is the only fly caspase known to be regulated by the hormone ecdysone. Here, we show that ectopic expression of dronc in the developing fly eye leads to increased cell death and an ablated eye phenotype that can be suppressed by halving the dosage of the genes in the H99 complex (reaper, hid and grim) and enhanced by mutations in diap1. In contrast to previous reports, we show that the dronc eye ablation phenotype can be suppressed by coexpression of the baculoviral caspase inhibitor p35. Dronc also interacts, both genetically and biochemically, with the CED-4/Apaf-1 fly homolog, Dark. Furthermore, extracts made from Dark homozygous mutant flies, have reduced ability to process Dronc, showing that Dark is required for Dronc processing. Finally, using RNA interference technique, we show that loss of Dronc function in early Drosophila embryos results in a drammatic decrease in cell death indicating that Dronc is important for programmed cell death during embryogenesis. These results suggest that Dronc is a key caspase mediating programmed cell death in Drosophila.

Human Molecular Genetics, 2004

Huntington's disease (HD) is caused by expansion of a polyglutamine tract near the N-terminal of ... more Huntington's disease (HD) is caused by expansion of a polyglutamine tract near the N-terminal of huntingtin. Mutant huntingtin forms aggregates in striatum and cortex, where extensive cell death occurs. We used a Drosophila polyglutamine peptide model to assess the role of specific cell death regulators in polyglutamine-induced cell death. Here, we report that polyglutamine-induced cell death was dramatically suppressed in flies lacking Dark, the fly homolog of human Apaf-1, a key regulator of apoptosis. Dark appeared to play a role in the accumulation of polyglutamine-containing aggregates. Suppression of cell death, caspase activation and aggregate formation were also observed when mutant huntingtin exon 1 was expressed in homozygous dark mutant animals. Expanded polyglutamine induced a marked increase in expression of Dark, and Dark was observed to colocalize with ubiquitinated protein aggregates. Apaf-1 also was found to colocalize with huntingtin-containing aggregates in a murine model and HD brain, suggesting a common role for Dark/ Apaf-1 in polyglutamine pathogenesis in invertebrates, mice and man. These findings suggest that limiting Apaf-1 activity may alleviate both pathological protein aggregation and neuronal cell death in HD.

Genes & Development, 2013

It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also ... more It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also drives nonapoptotic caspase activation to remodel cells. However, the determinants that specify whether the apoptosome acts to kill or remodel have yet to be identified. Here we report that Tango7 collaborates with the Drosophila apoptosome to drive a caspase-dependent remodeling process needed to resolve individual sperm from a syncytium. In these cells, Tango7 is required for caspase activity and localizes to the active apoptosome compartment via its C terminus. Furthermore, Tango7 directly stimulates the activity of this complex in vitro. We propose that Tango7 specifies the Drosophila apoptosome as an effector of cellular remodeling.

Genes & Development, 1995

Deletions of chromosomal region, 75C1,2 block virtually all programmed cell death (PCD) in the Dr... more Deletions of chromosomal region, 75C1,2 block virtually all programmed cell death (PCD) in the Drosophila embryo. We have identified a gene previously in this interval, reaper (rpr), which encodes an important regulator of PCD. Here we report the isolation of a second gene in this region, head involution defective (hid), which plays a similar role in PCD. hid mutant embryos have decreased levels of cell death and contain extra cells in the head. We have cloned the hid gene and find that its expression is sufficient to induce PCD in cell death defective mutants. The hid gene appears to encode a novel 410-amino-acid protein, and its mRNA is expressed in regions of the embryo where cell death occurs. Ectopic expression of hid in the Drosophila retina results in eye ablation. This phenotype can be suppressed completely by expression of the anti-apoptotic p35 protein from baculovirus, indicating that p35 may act genetically downstream from hid.

EMBO reports, 2000

The Drosophila innate immune system discriminates between pathogens and responds by inducing the ... more The Drosophila innate immune system discriminates between pathogens and responds by inducing the expression of specific antimicrobial peptide-encoding genes through distinct signaling cascades. Fungal infection activates NF-κB-like transcription factors via the Toll pathway, which also regulates innate immune responses in mammals. The pathways that mediate antibacterial defenses, however, are less defined. We have isolated loss-offunction mutations in the caspase encoding gene dredd, which block the expression of all genes that code for peptides with antibacterial activity. These mutations also render flies highly susceptible to infection by Gram-negative bacteria. Our results demonstrate that Dredd regulates antibacterial peptide gene expression, and we propose that Dredd, Immune Deficiency and the P105-like rel protein Relish define a pathway that is required to resist Gram-negative bacterial infections.

Developmental Biology, 1998

Caspases are widely conserved proteases considered to be essential effectors of apoptosis. We ide... more Caspases are widely conserved proteases considered to be essential effectors of apoptosis. We identified a novel Drosophila gene, dredd, which shares extensive homology to all members of the caspase gene family. Cells specified for programmed death in development exhibit a striking accumulation of dredd RNA that requires signaling by the death activators REAPER, GRIM, and HID. Furthermore, directed misexpression of each activator was sufficient to drive ectopic accumulation of dredd RNA. Heterozygosity at the dredd locus suppressed apoptosis in transgenic models of reaper-and grim-induced cell killing, demonstrating that levels of dredd product can modulate signaling triggered by these death activators. Finally, expression of REAPER, GRIM, and HID was found to trigger processing of DREDD protein precursor through a mechanism that is insensitive to, and upstream of, known caspase inhibitors. Taken together, these observations establish mechanistic connections between activators of apoptosis and a new downstream death effector in Drosophila.

Developmental Biology, 1996

The product of the reaper (rpr) gene is required for programmed cell death in Drosophila. We exam... more The product of the reaper (rpr) gene is required for programmed cell death in Drosophila. We examined rpr expression during ectopic cell deaths caused by ionizing radiation or aberrant development. In both instances, dramatic induction of rpr expression was observed. A genomic fragment upstream of rpr confers this regulatory behavior upon a lacZ reporter transgene. In a model cell culture system, conditional expression of REAPER is sufficient to induce massive apoptosis that can be prevented by the anti-apoptotic protein p35. Overall, these results suggest that diverse signals converge at, or upstream of, rpr-associated transcriptional regulatory elements that can function to initiate a common apoptotic pathway involving ICE-like protease activity.