Msx2 Is a Transcriptional Regulator in the BMP4-Mediated Programmed Cell Death Pathway

Cell Size: A Matter of Life or Death?

Regulation of cell death is among the most crucial tasks in the life of a cell. Recent data point to a complex regulatory system, composed of many signaling steps. Recent isolation of mutant arabidopsis and maize plants that undergo spontaneous cell death in unstimulated leaves implies that the cell death process is under genetic control (Dietrich et al., 1994; Greenberg et al., 1994). Many different stimuli have been shown to induce the process of programmed cell death (PCD) in a variety of plant species. The PCD response that occurs during the hypersensitive reaction of plants to avirulent pathogens is one of the most studied systems. When plants “sense” an infection by avirulent pathogens they begin to produce reactive oxygen species (ROS) that can trigger the cell death program in the reacting cells (Lamb and Dixon, 1997). Previous work has shown that the induction of PCD occurs only after the ROS have accumulated to a certain threshold value (Levine et al., 1994). Once however, the PCD has been activated, the initial stimulus can be removed without affecting the final outcome.KeywordsProgramme Cell DeathCysteine ProteasePlant Programme Cell DeathAvirulent PathogenSpontaneous Cell DeathThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Chapter 33 - Inflammasomes as integral components of PANoptosomes in the regulation of cell death

Stress in the endoplasmic reticulum caused by tunicamycin, dithiothreitol, and azole-class antifungal drugs can induce nonapoptotic cell death in yeasts that can be blocked by the action of calcineurin (Cn), a Ca(2+)-dependent serine/threonine protein phosphatase. To identify additional factors that regulate nonapoptotic cell death in yeast, a collection of gene knock-out mutants was screened for mutants exhibiting altered survival rates. The screen revealed an endocytic protein (Ede1) that can function upstream of Ca(2+)/calmodulin-dependent protein kinase 2 (Cmk2) to suppress cell death in parallel to Cn. The screen also revealed the vacuolar H(+)-ATPase (V-ATPase), which acidifies the lysosome-like vacuole. The V-ATPase performed its death-promoting functions very soon after imposition of the stress and was not required for later stages of the cell death program. Cn did not inhibit V-ATPase activities but did block vacuole membrane permeabilization (VMP), which occurred at late stages of the cell death program. All of the other nondying mutants identified in the screens blocked steps before VMP. These findings suggest that VMP is the lethal event in dying yeast cells and that fungi may employ a mechanism of cell death similar to the necrosis-like cell death of degenerating neurons.

Reply From Authors: How a cell dies matters and how to evaluate it also matters

: Programmed cell death (apoptosis) plays an essential role in maintaining the physiological balance of appropriate cell numbers by opposing uncontrolled cell proliferation. The pathway of programmed cell death appears to be highly conserved from C. elegans to humans, suggesting that studies of programmed cell death in C. elegans can provide important information for understanding how cell death is regulated and executed in humans. Moreover, novel means developed in C. elegans to modulate programmed cell death may also be applied to humans for better detection, prevention as well as treatment of human diseases caused by abnormal apoptosis (e.g. cancer, autoimmune disorders, and neurodegenerative diseases). In this study, we are employing the technique of SELEX (Systematic evolution of ligands by exponential amplification) to identify small RNA aptamers with high binding specificity and affinity for key cell death regulators, including CED-9 and CEDA-4 from C. elegans and Bcl-2 and Bcl-xL from humans. We hope to use these RNA aptamers to probe how Bcl-2 family proteins regulate programmed cell death in both C. elegans and mammalian cells. Importantly, if these RNA aptamers can be used to modulate apoptosis in C. elegans or mammalian cells, they may provide important insights into devising new diagnostic and therapeutic drugs to treat cancer and various apoptosis-related diseases. So far, we have successfully obtained RNA aptamers that bind CED-9 with Kds of approximately 10 nM. This high binding affinity will allow us to further study the effects of these aptamers in regulating apoptosis using both in vitro and in vivo assays: We have also conducted several rounds of SELEX experiments on CEDA and Bcl-xL and have obtained candidate molecules with increasing binding affinity in vitro to these two proteins.

The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. As the transit-amplifying progenitors of the intestinal epithelium generate ~300 cells per crypt every day, regulated cell death and sloughing at the apical surface keeps the overall cell number in check. An aberrant increase in the rate of intestinal epithelial cell (IEC) death underlies instances of extensive epithelial erosion, which is characteristic of several intestinal diseases such as inflammatory bowel disease and infectious colitis. Emerging evidence points to a crucial role of necroptosis, autophagy and pyroptosis as important modes of programmed cell death in the intestine in addition to apoptosis. The mode of cell death affects tissue restitution responses and ultimately the long-term risks of intestinal fibrosis and colorectal cancer. A vicious cycle of intestinal barrier breach, misregulated cell death and subsequent inflammation is at the heart of chronic inflammatory and infectious gastrointestinal diseases. This Review discusses the underlying molecular and cellular underpinnings that control programmed cell death in IECs, which emerge during intestinal diseases. Translational aspects of cell death modulation for the development of novel therapeutic alternatives for inflammatory bowel diseases and colorectal cancer are also discussed.

Programmed cell death in mammary tissue was studied during natural weaning in lactating mice and after litter removal or milk stasis. All treatments stimulated mammary apoptosis, indicating that this process is an integral part of the tissue's involution after lactation. Induction of apoptosis was slower in natural weaning than after litter removal but occurred earlier when mice were concurrently pregnant during natural weaning. Ipsilateral induction of apoptosis by milk stasis in teat-sealed glands indicates that cell death is under local (i.e., intramammary) as well as endocrine regulation. Apoptosis detected by DNA laddering was associated with changes in expression of p53 and bax, two genes implicated in the regulation of cell death, and was accompanied by structural degeneration characteristic of mammary involution. Reciprocal changes in stromelysin mRNA, and that of its inhibitor TIMP-2, suggested that this structural reorganisation was the result of coordinated changes in gene expression favouring proteolysis of the extracellular matrix.

Ice plant (Mesembryanthemum crystallinum L.) is a model plant for studying salt-tolerance mechanism in higher plants. The unique responses for salinity tolerance of ice plant can be induced at specific developmental stages. McCPN1, a plant-specific RING-type copine, is identified from halophyte Mesembryanthemum crystallinum L. and has a copine vWA domain at the N-terminus for protein-protein interaction and a C-terminal really interesting new gene (RING)-finger domain which contains ubiquitin E3 ligase activity. McCPN1 interacts and ubiquitinates a salt-induced protein McSKD1, a protein involving in protein trafficking. McCPN1 has high similarity to AtRGLG2, an E3 ligase mediates auxin transport and salt and drought stress response in Arabidopsis. To explore the role of McCPN1 in the salt stress adaptation process of ice plant, full-length McCPN1 was used as a bait to perform yeast two hybrid (Y2H) screen in the cDNA library constructed from roots of salt-treated ice plant. There were 120 candidate proteins identified from Y2H screening and eight candidates, E3, E9, E35, E36, E45, E46, E65 and E67 were chosen to determine the DNA sequences, after nutrition screening and β-galactosidase activity assays. Candidate E3 and E9 were Argonaute 4 (AGO4) which participates in small RNAs interference-mediated regulation of genes expression. E35 was a galactose-binding protein with galactose-binding domain-like and Sad 1/ UNC-like (SUN) C-terminal domain and, based on domain analysis, involved in cell adhesion, proliferation, apoptosis, nuclear anchoring and migration, and pre-mRNA splicing. E36 was xyloglucan endotransglucosylase/hydrolases and participates in cell wall extensibility, abscission, fruit growth, ripening and softening. E45 was DCD (Development and Cell Death) domain protein which interacts with cytoskeleton proteins for its movement and participates in programmed cell death under endoplasmic reticulum stress and osmotic stress. E46 was 26S ribosomal RNA in DNA blasting and unknown function protein of maize in protein sequence searching. E65 was heat shock protein 70 and responsible for proteins folding, refolding, transport and degradation in lysosomes or proteasomes and preventing protein aggregation. E67 was SPIKE1 protein which mediates tissue organization, cell morphology by controlling cytoskeleton microtubule, vesicle trafficking from the ER to Golgi in early secretory pathway homeostasis. According to Y2H result, McCPN1 can interact with candidate proteins to regulate cell morphology, development, death processes, and help protein trafficking, refolding and degradation after salt stress through ubiquitination. Cellular localization of McCPN1-YFP fusion protein was found in the plasma membrane, ER and Golgi, and distributed over the cytoplasm. The result suggests that McCPN1 widely distributes in several compartments and participates the ubiquitination process in these campartments. Candidates E3 and E9 blasted as AGO4 were chosen for further analyses. Full-length McAGO4 was identified by rapid amplification of cDNA ends (RACE). The domain analysis showed it has an amino-terminal domain DUF1785, a central PAZ domain and PIWI domain at C-terminus. Full-length McCPN1 and full-length McAGO4 have weak interaction as shown by pair-wise Y2H, pull-down assay, protoplast two-hybrid and bimolecular fluorescence complementation (BiFC). The weak protein-protein interaction might be the result of steric hindrance between two proteins. It is known that AGO4 locates at the nucleus and is involved in RNA-directed DNA methylation (RdDM). The BiFC results showed McCPN1 and McAGO4 colocalized at the nucleus suggesting that cytoplasmic localized McCPN1 moves to the nucleus to participate McAGO4-mediated gene silencing. In conclusion, McCPN1 is involved in many salt stress responses and one of them is to modulate McAGO4 activity by ubiquitination and changes gene expression profiles to increase salt tolerance of ice plant.

The work by Jog and Caricchio, 1 recently published in Cell Death and Disease, hypothesized an inherent difference in the cell death program between the sexes.In particular, they demonstrate that bone marrow-derived macrophages from male and female mice are prone to different types of cell death.Necrosis in cells from males is PARP-1 dependent, and inhibition of PARP-1 triggers the apoptotic cell death program.By contrast, in cells from females, cell death is PARP-1 independent.In addition, estrogens have a survival activity in female cells only, independent of estrogen receptor (ER) expression.Thus, estrogens and PARP-1 seem to represent two important determinants of the sex bias in cell death.Therefore, these authors propose that targeting cell death on the basis of sex will lead to tailored and better treatments for each gender.This is in line with a great challenge of the recently developed field of investigation dealing with the biology of sex differences and, more in general, with the socalled gender medicine. 2The main scope of this research field is aimed at the development of a made-to-measure pharmacologic approach that, taking into account gender disparity, could provide new and successful therapeutic strategies. 3,4We perfectly agree with these assumptions.The basis of this theory stems, in fact, on some recently published papers dealing with the role of 'cell sex' (i.e., freshly isolated cells with XX or XY chromosomes) in the susceptibility to cell death induction.In these studies, it was underscored that several key differences exist between XX and XY cells in this regard.Main features that have been suggested to display a gender disparity at cellular level are the following: (i) the basal redox state 5 ; (ii) the response to oxidative imbalance 6,7 ; (iii) the susceptibility to undergo apoptosis and anoikis 8,9 ; (iv) the susceptibility to undergo autophagy. 10These insights derived from several in vitro studies carried out in human and mouse cells of different histotypes including, for example, human endothelial cells and mouse neurons. 11,12A key factor in this scenario is represented by the ER signaling pathway.ERs are very important regulators of a plethora of cellular events, including apoptosis and autophagy, and can be expressed by both XX and XY cells at similar levels.Briefly, at least two types of ERs have been described (a and b), and the preponderance of one of these ERs over the other might change the impact of estrogen activity. 10,13,14As mentioned above, Jog and Caricchio 1

Programmed cell death (PCD) is the physiological death of a cell mediated by an intracellular suicide program. Although key components of the PCD execution pathway have been identified, how PCD is regulated during development is poorly understood. Here, we report that the epidermal growth factor (EGF)-like ligand LIN-3 acts as an extrinsic signal to promote the death of specific cells in Caenorhabditis elegans. The loss of LIN-3 or its receptor, LET-23, reduced the death of these cells, while excess LIN-3 or LET-23 signaling resulted in an increase in cell deaths. Our molecular and genetic data support the model that the LIN-3 signal is transduced through LET-23 to activate the LET-60/RAS-MPK-1/ERK MAPK pathway and the downstream ETS domain-containing transcription factor LIN-1. LIN-1 binds to, and activates transcription of, the key pro-apoptotic gene egl-1, which leads to the death of specific cells. Our results provide the first evidence that EGF induces PCD at the whole organism level and reveal the molecular basis for the death-promoting function of LIN-3/EGF. In addition, the level of LIN-3/EGF signaling is important for the precise fine-tuning of the life-versus-death fate. Our data and the previous cell culture studies that say EGF triggers apoptosis in some cell lines suggest that the EGF-mediated modulation of PCD is likely conserved in C. elegans and humans.

Programmed cell death (PCD), a regulated cell death (RCD) subtype essential for physiological homeostasis, encompasses distinct mechanisms including apoptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and pyroptosis. This evolutionarily conserved process critically regulates disease pathogenesis across degenerative disorders, malignancies, fungal infections, and vascular calcification (VC). VC manifests as pathological calcium deposition in cardiovascular tissues, impairing vascular elasticity and hemodynamics. These structural alterations elevate risks of atherosclerotic events, cerebrovascular accidents, and peripheral vascular dysfunction, while concomitantly inducing vital organ hypoperfusion and cardiac overload that predispose individuals to myocardial ischemia, left ventricular hypertrophy, and heart failure. Despite advances in delineating associated signaling networks, the molecular etiology of VC remains elusive, and effective therapeutic interventions are currently lacking. While systematically examining the pathophysiological contributions of both established and novel PCD mechanisms to VC progression, this review incorporates a discussion of cuproptosis as a novel form of PCD, which may serve as a target for atherosclerosis treatment. The inclusion of cuproptosis, alongside other PCD modalities, allows for a more integrated and updated perspective on the complex regulatory networks governing VC. Our objective is to synthesize the current understanding of how these diverse PCD pathways, both classical and emerging, collectively contribute to the disease pathogenesis and to explore the broader therapeutic potential of targeting PCD in VC.

Emerging role and interplay of programmed cell death in endometritis: Insights into mechanisms and therapeutic targets.

Research background: The Arabidopsis-resistance protein L5 (AT1G12290) can trigger cell death in Nicotiana benthamiana, which is a characteristic function of an NBS-LRR (Nucleotide-Binding Sites and Leucine-Rich Repeat) protein activation. Purpose: To explore the function and molecular regulatory network of L5. Method: We employed yeast two-hybrid technology to search for interacting proteins of L5, combined with laser confocal microscopy to observe the subcellular localization of these candidate proteins, and analyzed the impact of these proteins on L5 function using an Agrobacterium mediated transient expression system. Results: Seven candidate interacting proteins were identified from the Arabidopsis cDNA library, including PPA1 (AT1G01050), RIN4 (AT3G25070), LSU1 (AT3G49580), BZIP24 (AT3G51960), BOI (AT4G19700), RING/U (AT4G22250) and PPA3 (AT2G46860). Functional analysis of these candidate interacting proteins showed that they participated in multiple pathways, including biological and abiotic stress, programmed cell death, protein degradation, material metabolism and transcriptional regulation. The results of laser confocal microscopy manifested that RIN4 was only localized on the plasma membrane (PM), and RING/U was mainly associated with the PM. PPA1, PPA3, LSU1, BZIP24, and BOI all emerged nuclear and cytoplasmic localization. The results of the transient assay proclaimed that both BOI and RING/U can inhibit cell death caused by L5. Conclusions: These results indicate that L5 immune receptors may participate in various pathways, and their protein levels and activities are strictly regulated at multiple levels, providing a basis for elucidating the mechanism of L5 immune receptors in Arabidopsis resistance.

If pathophysiology were a fan propeller, cell death would constitute the pivot. Indeed, most diseases are connected to deregulated cell death in some way. Excessive, unwarranted cell death accounts for pathological cell loss, be it slowly degenerative as in Alzheimer's disease or dramatically acute as in stroke and myocardial infarction. Infectious pathogens manipulate cell death pathways to induce or inhibit the death of host cells at will and to subvert the immune recognition of ‘dangerous’ cell death. Finally, cancer is inexorably linked to a partial suppression of cell death programs in tumor cells, although therapy aims to (re)activate such lethal programs. Cell Death and Disease, a new open-access, online journal aims to provide center stage to fundamental, disease-oriented and translational research in cell death. [Opening paragraph]