scholarly journals Exogenous Introduction of Initiator and Executioner Caspases Results in Different Apoptotic Outcomes

JACS Au ◽  
2021 ◽  
Author(s):  
Francesca Anson ◽  
S. Thayumanavan ◽  
Jeanne A. Hardy
Keyword(s):  
Executioner Caspases

scholarly journals A New Pentafluorothio-Substituted Curcuminoid with Superior Antitumor Activity

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 947
Author(s):  
Benedikt Linder ◽  
Leonhard H. F. Köhler ◽  
Lisa Reisbeck ◽  
Dominic Menger ◽  
Dharmalingam Subramaniam ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Cell ◽  
Cell Lines ◽  
Human Tumor ◽  
Colon Adenocarcinoma ◽  
Tumor Cell Lines ◽  
Noticeable Increase ◽  
Ic50 Values ◽  
Executioner Caspases ◽  
G1 Cells

A new and readily available pentafluorothiophenyl-substituted N-methyl-piperidone curcuminoid 1a was prepared and investigated for its anti-proliferative, pro-apoptotic and cancer stem cell-differentiating activities against a panel of human tumor cell lines derived from various tumor entities. The compound 1a was highly anti-proliferative and reached IC50 values in the nanomolar concentration range. 1a was superior to the known anti-tumorally active curcuminoid EF24 (2) and its known N-ethyl-piperidone analog 1b in all tested tumor cell lines. Furthermore, 1a induced a noticeable increase of intracellular reactive oxygen species in HT-29 colon adenocarcinoma cells, which possibly leads to a distinct increase in sub-G1 cells, as assessed by cell cycle analysis. A considerable activation of the executioner-caspases 3 and 7 as well as nuclei fragmentation, cell rounding, and membrane protrusions suggest the triggering of an apoptotic mechanism. Yet another effect was the re-organization of the actin cytoskeleton shown by the formation of stress fibers and actin aggregation. 1a also caused cell death in the adherently cultured glioblastoma cell lines U251 and Mz54. We furthermore observed that 1a strongly suppressed the stem cell properties of glioma stem-like cell lines including one primary line, highlighting the potential therapeutic relevance of this new compound.

scholarly journals Phylogenetic analysis of the caspase family in bivalves: implications for programmed cell death, immune response and development

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Susanne Vogeler ◽  
Stefano Carboni ◽  
Xiaoxu Li ◽  
Alyssa Joyce
Keyword(s):  
Immune Response ◽  
Caspase 3 ◽  
Developmental Stages ◽  
Phylogenetic Analyses ◽  
Apoptotic Pathway ◽  
Caspase Family ◽  
Executioner Caspases ◽  
And Function ◽  
Relationship Of ◽  
Inflammatory Caspases

Abstract Background Apoptosis is an important process for an organism’s innate immune system to respond to pathogens, while also allowing for cell differentiation and other essential life functions. Caspases are one of the key protease enzymes involved in the apoptotic process, however there is currently a very limited understanding of bivalve caspase diversity and function. Results In this work, we investigated the presence of caspase homologues using a combination of bioinformatics and phylogenetic analyses. We blasted the Crassostrea gigas genome for caspase homologues and identified 35 potential homologues in the addition to the already cloned 23 bivalve caspases. As such, we present information about the phylogenetic relationship of all identified bivalve caspases in relation to their homology to well-established vertebrate and invertebrate caspases. Our results reveal unexpected novelty and complexity in the bivalve caspase family. Notably, we were unable to identify direct homologues to the initiator caspase-9, a key-caspase in the vertebrate apoptotic pathway, inflammatory caspases (caspase-1, − 4 or − 5) or executioner caspases-3, − 6, − 7. We also explored the fact that bivalves appear to possess several unique homologues to the initiator caspase groups − 2 and − 8. Large expansions of caspase-3 like homologues (caspase-3A-C), caspase-3/7 group and caspase-3/7-like homologues were also identified, suggesting unusual roles of caspases with direct implications for our understanding of immune response in relation to common bivalve diseases. Furthermore, we assessed the gene expression of two initiator (Cg2A, Cg8B) and four executioner caspases (Cg3A, Cg3B, Cg3C, Cg3/7) in C. gigas late-larval development and during metamorphosis, indicating that caspase expression varies across the different developmental stages. Conclusion Our analysis provides the first overview of caspases across different bivalve species with essential new insights into caspase diversity, knowledge that can be used for further investigations into immune response to pathogens or regulation of developmental processes.

scholarly journals Microfluidic deep mutational scanning of the human executioner caspases reveals differences in structure and regulation

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Hridindu Roychowdury ◽  
Philip A. Romero
Keyword(s):  
Large Scale ◽  
Cysteine Proteases ◽  
Amino Acid Substitutions ◽  
Substrate Preferences ◽  
Functional Differences ◽  
Caspase Family ◽  
Executioner Caspases ◽  
The Impact ◽  
Human Caspase

AbstractThe human caspase family comprises 12 cysteine proteases that are centrally involved in cell death and inflammation responses. The members of this family have conserved sequences and structures, highly similar enzymatic activities and substrate preferences, and overlapping physiological roles. In this paper, we present a deep mutational scan of the executioner caspases CASP3 and CASP7 to dissect differences in their structure, function, and regulation. Our approach leverages high-throughput microfluidic screening to analyze hundreds of thousands of caspase variants in tightly controlled in vitro reactions. The resulting data provides a large-scale and unbiased view of the impact of amino acid substitutions on the proteolytic activity of CASP3 and CASP7. We use this data to pinpoint key functional differences between CASP3 and CASP7, including a secondary internal cleavage site, CASP7 Q196 that is not present in CASP3. Our results will open avenues for inquiry in caspase function and regulation that could potentially inform the development of future caspase-specific therapeutics.

scholarly journals Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

2018 ◽  
Author(s):  
R. N. V. Krishna Deepak ◽  
Ahmad Abdullah ◽  
Priti Talwar ◽  
Hao Fan ◽  
Palaniyandi Ravanan
Keyword(s):  
Active Site ◽  
Caspase 3 ◽  
Specific Activity ◽  
Special Importance ◽  
Allosteric Inhibitors ◽  
Dimerization Interface ◽  
Executioner Caspases ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractThe regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed five compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that four out of the five drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the four compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

scholarly journals Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

2018 ◽  
Vol 86 (11) ◽  
pp. 1202-1210 ◽  
Author(s):  
R. N. V. Krishna Deepak ◽  
Ahmad Abdullah ◽  
Priti Talwar ◽  
Hao Fan ◽  
Palaniyandi Ravanan
Keyword(s):  
Allosteric Inhibitors ◽  
Executioner Caspases ◽  
Approved Drugs ◽  
Fda Approved Drugs

scholarly journals Activation of the executioner caspases-3 and -7 promotes microglial pyroptosis in models of multiple sclerosis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Brienne A. McKenzie ◽  
Jason P. Fernandes ◽  
Matthew A. L. Doan ◽  
Laura M. Schmitt ◽  
William G. Branton ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Executioner Caspases

scholarly journals Post-transcriptional control of executioner caspases by RNA-binding proteins

2016 ◽  
Vol 30 (19) ◽  
pp. 2213-2225 ◽  
Author(s):  
Deni Subasic ◽  
Thomas Stoeger ◽  
Seline Eisenring ◽  
Ana M. Matia-González ◽  
Jochen Imig ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Executioner Caspases

scholarly journals Doxorubicin Differentially Induces Apoptosis, Expression of Mitochondrial Apoptosis-Related Genes, and Mitochondrial Potential in BCR-ABL1-Expressing Cells Sensitive and Resistant to Imatinib

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Ewelina Synowiec ◽  
Grazyna Hoser ◽  
Jolanta Bialkowska-Warzecha ◽  
Elzbieta Pawlowska ◽  
Tomasz Skorski ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Nadh Dehydrogenase ◽  
Genotoxic Stress ◽  
Mitochondrial Potential ◽  
Imatinib Resistance ◽  
Imatinib Resistant ◽  
Executioner Caspases ◽  
Apoptosis Inducing Factor ◽  
Increased Activity ◽  
Higher Sensitivity

Imatinib resistance is an emerging problem in the therapy of chronic myeloid leukemia (CML). Because imatinib induces apoptosis, which may be coupled with mitochondria and DNA damage is a prototype apoptosis-inducing factor, we hypothesized that imatinib-sensitive and -resistant CML cells might differentially express apoptosis-related mitochondrially encoded genes in response to genotoxic stress. We investigated the effect of doxorubicin (DOX), a DNA-damaging anticancer drug, on apoptosis and the expression of the mitochondrial NADH dehydrogenase 3 (MT-ND3) and cytochromeb(MT-CYB) in model CML cells showing imatinib resistance caused by Y253H mutation in theBCR-ABL1gene (253) or culturing imatinib-sensitive (S) cells in increasing concentrations of imatinib (AR). The imatinib-resistant 253 cells displayed higher sensitivity to apoptosis induced by 1 μM DOX and this was confirmed by an increased activity of executioner caspases 3 and 7 in those cells. Native mitochondrial potential was lower in imatinib-resistant cells than in their sensitive counterparts and DOX lowered it. MT-CYB mRNA expression in 253 cells was lower than that in S cells and 0.1 μM DOX kept this relationship. In conclusion, imatinib resistance may be associated with altered mitochondrial response to genotoxic stress, which may be further exploited in CML therapy in patients with imatinib resistance.

Caspase activation

2003 ◽  
Vol 70 ◽  
pp. 233-242 ◽  
Author(s):  
Kelly M. Boatright ◽  
Guy S. Salvesen
Keyword(s):  
Cell Death ◽  
Recent Work ◽  
Proteolytic Cleavage ◽  
Caspase Activation ◽  
Point Of No Return ◽  
Initiator Caspases ◽  
Executioner Caspases ◽  
Activation Event

Caspase activation is the 'point of no return' commitment to cell death. Synthesized as inactive zymogens, it is essential that the caspases remain inactive until the death signal is received. It is known for the downstream executioner caspases-3 and -7 that the activation event is proteolytic cleavage, and this had been assumed to apply to the initiator caspases as well. However, recent studies conducted on caspases-2, -8 and -9 have challenged this tenet of caspase activation. In this review we focus on the molecular details of caspase activation, with emphasis on recent work that provides a pleasing explanation for the differential requirements for the activation of executioner and initiator caspases.

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