scholarly journals Chemical Genetics Approach Identifies Abnormal Inflorescence Meristem 1 as a Putative Target of a Novel Sulfonamide That Protects Catalase2-Deficient Arabidopsis against Photorespiratory Stress

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2026
Author(s):  
Tom van der Meer ◽  
Arno Verlee ◽  
Patrick Willems ◽  
Francis Impens ◽  
Kris Gevaert ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Affinity Purification ◽  
Signaling Cascades ◽  
Inflorescence Meristem ◽  
Scavenging Capacity ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Chemical Screen ◽  
Cell Death Phenotype

Alterations of hydrogen peroxide (H2O2) levels have a profound impact on numerous signaling cascades orchestrating plant growth, development, and stress signaling, including programmed cell death. To expand the repertoire of known molecular mechanisms implicated in H2O2 signaling, we performed a forward chemical screen to identify small molecules that could alleviate the photorespiratory-induced cell death phenotype of Arabidopsisthaliana mutants lacking H2O2-scavenging capacity by peroxisomal catalase2. Here, we report the characterization of pakerine, an m-sulfamoyl benzamide from the sulfonamide family. Pakerine alleviates the cell death phenotype of cat2 mutants exposed to photorespiration-promoting conditions and delays dark-induced senescence in wild-type Arabidopsis leaves. By using a combination of transcriptomics, metabolomics, and affinity purification, we identified abnormal inflorescence meristem 1 (AIM1) as a putative protein target of pakerine. AIM1 is a 3-hydroxyacyl-CoA dehydrogenase involved in fatty acid β-oxidation that contributes to jasmonic acid (JA) and salicylic acid (SA) biosynthesis. Whereas intact JA biosynthesis was not required for pakerine bioactivity, our results point toward a role for β-oxidation-dependent SA production in the execution of H2O2-mediated cell death.

scholarly journals Loss of the common immune coreceptor BAK1 leads to NLR-dependent cell death

2020 ◽  
Vol 117 (43) ◽  
pp. 27044-27053 ◽  
Author(s):  
Yujun Wu ◽  
Yang Gao ◽  
Yanyan Zhan ◽  
Hong Kui ◽  
Hongyan Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Pseudomonas Syringae ◽  
Molecular Mechanisms ◽  
Receptor Protein ◽  
Dependent Manner ◽  
Effector Triggered Immunity ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Death Phenotype ◽  
Recognition Receptor

Plants utilize a two-tiered immune system consisting of pattern recognition receptor (PRR)-triggered immunity (PTI) and effector-triggered immunity (ETI) to defend themselves against pathogenic microbes. The receptor protein kinase BAK1 plays a central role in multiple PTI signaling pathways in Arabidopsis. However, double mutants made by BAK1 and its closest paralog BKK1 exhibit autoimmune phenotypes, including cell death resembling a typical nucleotide-binding leucine-rich repeat protein (NLR)-mediated ETI response. The molecular mechanisms of the cell death caused by the depletion of BAK1 and BKK1 are poorly understood. Here, we show that the cell-death phenotype of bak1 bkk1 is suppressed when a group of NLRs, ADR1s, are mutated, indicating the cell-death of bak1 bkk1 is the consequence of NLR activation. Furthermore, introduction of a Pseudomonas syringae effector HopB1, which proteolytically cleaves activated BAK1 and its paralogs via either gene transformation or bacterium-delivery, results in a cell-death phenotype in an ADR1s-dependent manner. Our study thus pinpoints that BAK1 and its paralogs are likely guarded by NLRs.

scholarly journals CBMT-44. COMPREHENSIVE CHARACTERIZATION OF THE INTRINSIC APOPTOTIC MACHINERY REVEALS THE MOLECULAR BLOCKS RESPONSIBLE FOR RESISTANCE TO CELL DEATH IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi42-vi42
Author(s):  
Elizabeth Fernandez ◽  
Wilson Mai ◽  
Nicholas Bayley ◽  
Linda Liau ◽  
Timothy Cloughesy ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Intrinsic Apoptosis ◽  
Wild Type ◽  
Apoptotic Protein ◽  
Orthotopic Xenografts ◽  
Comprehensive Characterization ◽  
Tumor Eradication ◽  
Poor Patient Survival

Abstract Conventional therapies (e.g., temozolomide (TMZ), Irradiation (IR)) transiently halt tumor growth of glioblastoma (GBM) but fail to induce cell death through apoptosis. Consequently, the inability to kill GBM tumor cells ultimately leads to disease progression and a poor patient survival. The precise molecular mechanisms by which GBM are refractory to apoptosis remain enigmatic. We preformed BH3 profiling to functionally characterize the intrinsic apoptotic machinery and define the molecular ‘blocks’ that obstruct GBM apoptosis under both basal and treatment states. Using a molecularly diverse panel of freshly purified patient tumors, patient-derived neurospheres and patient-derived orthotopic xenografts, we identified that nearly all GBMs have two anti-apoptotic blocks, BCL-xL and MCL-1, which are essential for GBM survival in an untreated state. TMZ or IR (TMZ/IR) disabled the MCL-1 block in a subset of GBMs, leaving tumors exclusively dependent on BCL-xL for survival. Mechanistic studies revealed that TMZ/IR treatment induced p53-dependent expression of the pro-apoptotic protein, PUMA, which subsequently bound to and neutralized MCL-1. Consequently, pharmacological inhibition of BCL-xL in combination with TMZ/IR initiated intrinsic apoptosis and was synergistically lethal in p53 wild-type GBM. These studies identify the existence of two anti-apoptotic proteins that are critical for GBM survival, which can be therapeutically exploited in a molecularly defined subset of GBMs for tumor eradication.

A screen for suppressors of apoptosis identifies a novel gain of function mutation in drosphilia RAS1s

2007 ◽  
Vol 30 (4) ◽  
pp. 82
Author(s):  
C Gafuik ◽  
J Agapite ◽  
H Steller
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Model Organisms ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Ras Oncogenes ◽  
Induced Apoptosis

Background: Apoptosis is a morphologically distinct, genetically programmed form of cell death that is evolutionarily highly conserved amongst multi-cellular eukaryotes. Correct regulation of apoptosis is critical for normal development and the prevention of diseases, such as cancer. Genetic analysis of invertebrate model organisms has proven invaluable for the identification and study of key molecules involved in apoptosis. In Drosophila, the proteins Reaper (Rpr), Head involution defective (Hid) and Grim induce cell death in a caspase dependent manner by inhibiting the anti-apoptotic function of diap1. Methods: To further elucidate the molecular mechanisms underlying the control of apoptosis, we conducted a dominant modifier screen for genes that could suppress the strong eye ablation phenotype caused by expressing hid under the control of an eye-specific promoter. Results: As previously reported, we identified several loss of function mutants in components of the EGFR/Ras/MAPK pathway that could dominantly suppress hid-induced apoptosis. These mutants proved to be alleles of either sprouty or gap1, two negative regulators of the RTK/Ras1 signaling. Here we report the identification and characterization of the first gain of function mutation in the Drosophila RAS1 gene. Conclusions: Taken together, these findings provide a molecular paradigm for the anti-apoptotic function of ras oncogenes.

scholarly journals Therapy-Induced Tumor Cell Death: Friend or Foe of Immunotherapy?

2021 ◽  
Vol 11 ◽  
Author(s):  
Thijs A. van Schaik ◽  
Kok-Siong Chen ◽  
Khalid Shah
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Molecular Mechanisms ◽  
Significant Proportion ◽  
Local Environment ◽  
Signaling Cascades ◽  
Tumor Cell Death ◽  
Adequate Treatment ◽  
Immunosuppressive Tumor Microenvironment ◽  
The Impact

Combinatory treatments using surgery, radiotherapy and/or chemotherapy together with immunotherapy have shown encouraging results for specific subsets of tumors, but a significant proportion of tumors remains unsusceptible. Some of these inconsistencies are thought to be the consequence of an immunosuppressive tumor microenvironment (TME) caused by therapy-induced tumor cell death (TCD). An increased understanding of the molecular mechanisms governing TCD has provided valuable insights in specific signaling cascades activated by treatment and the subsequent effects on the TME. Depending on the treatment variables of conventional chemo-, radio- and immunotherapy and the genetic composition of the tumor cells, particular cell death pathways are activated. Consequently, TCD can either have tolerogenic or immunogenic effects on the local environment and thereby affect the post-treatment anti-tumor response of immune cells. Thus, identification of these events can provide new rationales to increase the efficacy of conventional therapies combined with immunotherapies. In this review, we sought to provide an overview of the molecular mechanisms initiated by conventional therapies and the impact of treatment-induced TCD on the TME. We also provide some perspectives on how we can circumvent tolerogenic effects by adequate treatment selection and manipulation of key signaling cascades.

Mechanisms of Regulated Cell Death: Current Perspectives

2021 ◽  
pp. 030098582110055
Author(s):  
Sara Francesca Santagostino ◽  
Charles-Antoine Assenmacher ◽  
James C. Tarrant ◽  
Adeyemi O. Adedeji ◽  
Enrico Radaelli
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Regulated Cell Death ◽  
Morphologic Characteristics ◽  
Adaptive Processes ◽  
Molecular Machinery ◽  
Extracellular Microenvironment ◽  
Apoptosis And Necrosis ◽  
Microscopic Findings

Balancing cell survival and cell death is fundamental to development and homeostasis. Cell death is regulated by multiple interconnected signaling pathways and molecular mechanisms. Regulated cell death (RCD) is implicated in fundamental processes such as organogenesis and tissue remodeling, removal of unnecessary structures or cells, and regulation of cell numbers. RCD can also be triggered by exogenous perturbations of the intracellular or extracellular microenvironment when the adaptive processes that respond to stress fail. During the past few years, many novel forms of non-apoptotic RCD have been identified, and the characterization of RCD mechanisms at a molecular level has deepened our understanding of diseases encountered in human and veterinary medicine. Given the complexity of these processes, it has become clear that the identification of RCD cannot be based simply on morphologic characteristics and that descriptive and diagnostic terms presently used by pathologists—such as individual cell apoptosis or necrosis—appear inadequate and possibly misleading. In this review, the current understanding of the molecular machinery of each type of non-apoptotic RCD mechanisms is outlined. Due to the continuous discovery of new mechanisms or nuances of previously described processes, the limitations of the terms apoptosis and necrosis to indicate microscopic findings are also reported. In addition, the need for a standard panel of biomarkers and functional tests to adequately characterize the underlying RCD and its role as a mechanism of disease is considered.

MALAT1 as a Versatile Regulator of Cancer: Overview of the updates from Predatory role as Competitive Endogenous RNA to Mechanistic In-sights

2020 ◽  
Vol 20 ◽  
Author(s):  
Ammad Ahmad Farooqi ◽  
Evangelia Legaki ◽  
Maria Gazouli ◽  
Silvia Rinaldi ◽  
Rossana Berardi
Keyword(s):  
Molecular Biology ◽  
Detailed Analysis ◽  
Signaling Pathways ◽  
Individualized Medicine ◽  
Signaling Cascades ◽  
Oncogenic Signaling ◽  
Non Coding Rnas ◽  
Oncogenic Signaling Pathways ◽  
Competitive Endogenous Rna

: Central dogma of molecular biology has remained cornerstone of classical molecular biology but serendipitous discovery of microRNAs (miRNAs) in nematodes paradigmatically shifted our current understanding of the intricate mech-anisms which occur during transitions from transcription to translation. Discovery of miRNA captured tremendous attention and appreciation and we had witnessed an explosion in the field of non-coding RNAs. Ground-breaking discoveries in the field of non-coding RNAs have helped in better characterization of microRNAs and long non-coding RNAs (LncRNAs). There is an ever-increasing list of miRNA targets which are regulated by MALAT1 to stimulate or repress expression of tar-get genes. However, in this review our main focus is to summarize mechanistic insights related to MALAT1-mediated regu-lation of oncogenic signaling pathways. We have discussed how MALAT1 modulated TGF/SMAD and Hippo pathways in various cancers. We have also comprehensively summarized how JAK/STAT and Wnt/β-catenin pathways stimulated MALAT1 expression and consequentially how MALAT1 potentiated these signaling cascades to promote cancer. MALAT1 research has undergone substantial broadening however, there is still a need to identify additional mechanisms. MALAT1 is involved in multi-layered regulation of multiple transduction cascades and detailed analysis of different pathways will be helpful in getting a step closer to individualized medicine.

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