scholarly journals Inhibition of Development of Myxococcus xanthus by Eukaryotic Protein Kinase Inhibitors

1998 ◽  
Vol 180 (24) ◽  
pp. 6544-6550 ◽  
Author(s):  
Ritu Jain ◽  
Sumiko Inouye
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Myxococcus Xanthus ◽  
Large Family ◽  
Protein Kinase Inhibitors ◽  
Specific Gene ◽  
Fruiting Bodies ◽  
Fruiting Body Formation ◽  
Eukaryotic Protein Kinase ◽  
Eukaryotic Protein

ABSTRACT Myxococcus xanthus is a social bacterium that lives in the soil and undergoes spectacular development to form multicellular fruiting bodies. It contains a large family of eukaryote-like serine/threonine protein kinases. We found that a number of inhibitors for eukaryotic protein serine, threonine, and tyrosine kinases could inhibit the development and sporulation of M. xanthus to various degrees. These results suggest that serine/threonine and tyrosine phosphorylation may be involved in development of M. xanthus. None of the inhibitors tested had any effect on vegetative growth of M. xanthus. Most of them seemed to act during the early stages of development. However, the expression of a very early development-specific gene, Ω4521, was not significantly affected by the inhibitors. The patterns of protein phosphorylation during development were also not significantly altered by the inhibitors, suggesting that the targets of the inhibitors are minor or unstable phosphoproteins but play key roles in fruiting-body formation in M. xanthus.

scholarly journals Screening of Microbial Extracts for Anticancer Compounds Using Streptomyces Kinase Inhibitor Assay

2015 ◽  
Vol 10 (7) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Prashant Shanbhag ◽  
Sarita Bhave ◽  
Ashwini Vartak ◽  
Asha Kulkarni-Almeida ◽  
Girish Mahajan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Kinase Assay ◽  
Diffusion Method ◽  
Eukaryotic Protein Kinase ◽  
Eukaryotic Protein ◽  
Microbial Extracts

Eukaryotic kinases are known to play an important role in signal transduction pathways by phosphorylating their respective substrates. Abnormal phosphorylations by these kinases have resulted in diseases. Hence inhibitors of kinases are of considerable pharmaceutical interest for a wide variety of disease targets, especially cancers. A number of reports have been published which indicate that eukaryotic-like kinases may complement two-component kinase systems in several bacteria. In Streptomyces sp. such kinases have been found to have a role in formation of aerial hyphae, spores, pigmentation & even in antibiotic production in some strains. Eukaryotic kinase inhibitors are seen to inhibit formation of aerial mycelia in Streptomyces without inhibiting vegetative mycelia. This property has been used to design an assay to screen for eukaryotic kinase inhibitors. The assay involves testing of compounds against Streptomyces 85E ATCC 55824 using agar well diffusion method. Inhibitors of kinases give rise to “bald” colonies where aerial mycelia and sporulation inhibition is seen. The assay has been standardized using known eukaryotic protein kinase inhibiting anticancer agents like AG-490, AG-1295, AG-1478, Flavopiridol and Imatinib as positive controls, at a concentration ranging from 10 μg/well to 100 μg/well. Anti-infective compounds which are not reported to inhibit eukaryotic protein kinases were used as negative controls. A number of microbial cultures have been screened for novel eukaryotic protein kinase inhibitors. Further these microbial extracts were tested in various cancer cell lines like Panc1, HCT116, Calu1, ACHN and H460 at a concentration of 10 μg/mL/ well. The anticancer data was seen correlating well with the Streptomyces kinase assay thus validating the assay.

scholarly journals Multicellular Development in Myxococcus xanthus Is Stimulated by Predator-Prey Interactions

2007 ◽  
Vol 189 (15) ◽  
pp. 5675-5682 ◽  
Author(s):  
James E. Berleman ◽  
John R. Kirby
Keyword(s):  
Fruiting Body ◽  
Prey Availability ◽  
Process Analysis ◽  
Myxococcus Xanthus ◽  
Stringent Response ◽  
Fruiting Bodies ◽  
Fruiting Body Formation ◽  
Multicellular Development ◽  
Body Formation ◽  
Body Development

ABSTRACT Myxococcus xanthus is a predatory bacterium that exhibits complex social behavior. The most pronounced behavior is the aggregation of cells into raised fruiting body structures in which cells differentiate into stress-resistant spores. In the laboratory, monocultures of M. xanthus at a very high density will reproducibly induce hundreds of randomly localized fruiting bodies when exposed to low nutrient availability and a solid surface. In this report, we analyze how M. xanthus fruiting body development proceeds in a coculture with suitable prey. Our analysis indicates that when prey bacteria are provided as a nutrient source, fruiting body aggregation is more organized, such that fruiting bodies form specifically after a step-down or loss of prey availability, whereas a step-up in prey availability inhibits fruiting body formation. This localization of aggregates occurs independently of the basal nutrient levels tested, indicating that starvation is not required for this process. Analysis of early developmental signaling relA and asgD mutants indicates that they are capable of forming fruiting body aggregates in the presence of prey, demonstrating that the stringent response and A-signal production are surprisingly not required for the initiation of fruiting behavior. However, these strains are still defective in differentiating to spores. We conclude that fruiting body formation does not occur exclusively in response to starvation and propose an alternative model in which multicellular development is driven by the interactions between M. xanthus cells and their cognate prey.

scholarly journals Aggregation during Fruiting Body Formation in Myxococcus xanthus Is Driven by Reducing Cell Movement

2006 ◽  
Vol 189 (2) ◽  
pp. 611-619 ◽  
Author(s):  
Oleksii Sliusarenko ◽  
David R. Zusman ◽  
George Oster
Keyword(s):  
Fruiting Body ◽  
Myxococcus Xanthus ◽  
Cell Movement ◽  
Fruiting Bodies ◽  
Fruiting Body Formation ◽  
Agent Based ◽  
Body Formation ◽  
Early Stages ◽  
Cell Velocity ◽  
Reversal Frequency

ABSTRACT When starved, Myxococcus xanthus cells assemble themselves into aggregates of about 105 cells that grow into complex structures called fruiting bodies, where they later sporulate. Here we present new observations on the velocities of the cells, their orientations, and reversal rates during the early stages of fruiting body formation. Most strikingly, we find that during aggregation, cell velocities slow dramatically and cells orient themselves in parallel inside the aggregates, while later cell orientations are circumferential to the periphery. The slowing of cell velocity, rather than changes in reversal frequency, can account for the accumulation of cells into aggregates. These observations are mimicked by a continuous agent-based computational model that reproduces the early stages of fruiting body formation. We also show, both experimentally and computationally, how changes in reversal frequency controlled by the Frz system mutants affect the shape of these early fruiting bodies.

scholarly journals An ambruticin-sensing complex modulates Myxococcus xanthus development and mediates myxobacterial interspecies communication

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Francisco Javier Marcos-Torres ◽  
Carsten Volz ◽  
Rolf Müller
Keyword(s):  
Myxococcus Xanthus ◽  
Cell Aggregation ◽  
Growth Conditions ◽  
Fruiting Bodies ◽  
Regulatory Pathway ◽  
Fruiting Body Formation ◽  
Histidine Kinases ◽  
Interspecies Communication ◽  
High Concentrations

Abstract Starvation induces cell aggregation in the soil bacterium Myxococcus xanthus, followed by formation of fruiting bodies packed with myxospores. Sporulation in the absence of fruiting bodies can be artificially induced by high concentrations of glycerol through unclear mechanisms. Here, we show that a compound (ambruticin VS-3) produced by a different myxobacterium, Sorangium cellulosum, affects the development of M. xanthus in a similar manner. Both glycerol (at millimolar levels) and ambruticin VS-3 (at nanomolar concentrations) inhibit M. xanthus fruiting body formation under starvation, and induce sporulation in the presence of nutrients. The response is mediated in M. xanthus by three hybrid histidine kinases (AskA, AskB, AskC) that form complexes interacting with two major developmental regulators (MrpC, FruA). In addition, AskB binds directly to the mrpC promoter in vitro. Thus, our work indicates that the AskABC-dependent regulatory pathway mediates the responses to ambruticin VS-3 and glycerol. We hypothesize that production of ambruticin VS-3 may allow S. sorangium to outcompete M. xanthus under both starvation and growth conditions in soil.

scholarly journals Developmental Aggregation of Myxococcus xanthus Requires frgA, anfrz-Related Gene

2000 ◽  
Vol 182 (23) ◽  
pp. 6614-6621 ◽  
Author(s):  
Kyungyun Cho ◽  
Anke Treuner-Lange ◽  
Kathleen A. O'Connor ◽  
David R. Zusman
Keyword(s):  
Fruiting Body ◽  
Myxococcus Xanthus ◽  
Complex Life Cycle ◽  
Fruiting Bodies ◽  
Related Gene ◽  
Wild Type ◽  
Fruiting Body Formation ◽  
Body Formation ◽  
Extracellular Signals ◽  
Directed Motility

ABSTRACT Myxococcus xanthus is a gram-negative bacterium which has a complex life cycle that includes multicellular fruiting body formation. Frizzy mutants are characterized by the formation of tangled filaments instead of hemispherical fruiting bodies on fruiting agar. Mutations in the frz genes have been shown to cause defects in directed motility, which is essential for both vegetative swarming and fruiting body formation. In this paper, we report the discovery of a new gene, called frgA (forfrz-related gene), which confers a subset of the frizzy phenotype when mutated. The frgA null mutant showed reduced swarming and the formation of frizzy aggregates on fruiting agar. However, this mutant still displayed directed motility in a spatial chemotaxis assay, whereas the majority offrz mutants fail to show directed movements in this assay. Furthermore, the frizzy phenotype of the frgA mutant could be complemented extracellularly by wild-type cells or strains carrying non-frz mutations. The phenotype of the frgAmutant is similar to that of the abcA mutant and suggests that both of these mutants could be defective in the production or export of extracellular signals required for fruiting body formation rather than in the sensing of such extracellular signals. ThefrgA gene encodes a large protein of 883 amino acids which lacks homologues in the databases. The frgA gene is part of an operon which includes two additional genes, frgBand frgC. The frgB gene encodes a putative histidine protein kinase, and the frgC gene encodes a putative response regulator. The frgB and frgCnull mutants, however, formed wild-type fruiting bodies.

scholarly journals Spatial Organization of Myxococcus xanthus during Fruiting Body Formation

2007 ◽  
Vol 189 (24) ◽  
pp. 9126-9130 ◽  
Author(s):  
Patrick D. Curtis ◽  
Rion G. Taylor ◽  
Roy D. Welch ◽  
Lawrence J. Shimkets
Keyword(s):  
Fruiting Body ◽  
Spatial Organization ◽  
Myxococcus Xanthus ◽  
Matrix Material ◽  
Cell Monolayer ◽  
Fruiting Bodies ◽  
Fruiting Body Formation ◽  
Quiescent Phase ◽  
Body Development ◽  
Uppermost Layer

ABSTRACT Microcinematography was used to examine fruiting body development of Myxococcus xanthus. Wild-type cells progress through three distinct phases: a quiescent phase with some motility but little aggregation (0 to 8 h), a period of vigorous motility leading to raised fruiting bodies (8 to 16 h), and a period of maturation during which sporulation is initiated (16 to 48 h). Fruiting bodies are extended vertically in a series of tiers, each involving the addition of a cell monolayer on top of the uppermost layer. A pilA (MXAN_5783) mutant produced less extracellular matrix material and thus allowed closer examination of tiered aggregate formation. A csgA (MXAN_1294) mutant exhibited no quiescent phase, aberrant aggregation in phase 2, and disintegration of the fruiting bodies in the third phase.

scholarly journals Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 12731
Author(s):  
Emilie Logie ◽  
Claudina Perez Novo ◽  
Amber Driesen ◽  
Pieter Van Vlierberghe ◽  
Wim Vanden Berghe
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Apoptotic Cell ◽  
Protein Kinase Inhibitors ◽  
Withaferin A ◽  
Myeloma Cells ◽  
Activity Profiling ◽  
Anti Cancer

Through phosphorylation of their substrate proteins, protein kinases are crucial for transducing cellular signals and orchestrating biological processes, including cell death and survival. Recent studies have revealed that kinases are involved in ferroptosis, an iron-dependent mode of cell death associated with toxic lipid peroxidation. Given that ferroptosis is being explored as an alternative strategy to eliminate apoptosis-resistant tumor cells, further characterization of ferroptosis-dependent kinase changes might aid in identifying novel druggable targets for protein kinase inhibitors in the context of cancer treatment. To this end, we performed a phosphopeptidome based kinase activity profiling of glucocorticoid-resistant multiple myeloma cells treated with either the apoptosis inducer staurosporine (STS) or ferroptosis inducer RSL3 and compared their kinome activity signatures. Our data demonstrate that both cell death mechanisms inhibit the activity of kinases classified into the CMGC and AGC families, with STS showing a broader spectrum of serine/threonine kinase inhibition. In contrast, RSL3 targets a significant number of tyrosine kinases, including key players of the B-cell receptor signaling pathway. Remarkably, additional kinase profiling of the anti-cancer agent withaferin A revealed considerable overlap with ferroptosis and apoptosis kinome activity, explaining why withaferin A can induce mixed ferroptotic and apoptotic cell death features. Altogether, we show that apoptotic and ferroptotic cell death induce different kinase signaling changes and that kinome profiling might become a valid approach to identify cell death chemosensitization modalities of novel anti-cancer agents.

scholarly journals Targeting Receptor Kinases in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 433 ◽  
Author(s):  
Marilina García-Aranda ◽  
Maximino Redondo
Keyword(s):  
Colorectal Cancer ◽  
Cancer Treatment ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Great Effort ◽  
Screening Programs ◽  
Common Cancer ◽  
Receptor Kinases ◽  
Common Malignancy

Colorectal cancer is the third most common malignancy in men and the second most common cancer in women. Despite the success of screening programs and the development of adjuvant therapies, the global burden of colorectal cancer is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. In recent years, a great effort has been made to demonstrate the utility of protein kinase inhibitors for cancer treatment. Considering this heterogeneous disease is defined by mutations that activate different Receptor Tyrosine Kinases (RTKs) and affect downstream components of RTK-activated transduction pathways, in this review we analyze the potential utility of different kinase inhibitors for colorectal cancer treatment.

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