scholarly journals Discrete Functions of TRAF1 and TRAF2 in Drosophila melanogaster Mediated by c-Jun N-Terminal Kinase and NF-κB-Dependent Signaling Pathways

2003 ◽  
Vol 23 (22) ◽  
pp. 7982-7991 ◽  
Author(s):  
Guang-Ho Cha ◽  
Kyoung Sang Cho ◽  
Jun Hee Lee ◽  
Myungjin Kim ◽  
Euysoo Kim ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Signaling Pathways ◽  
Nuclear Translocation ◽  
Genetic Interaction ◽  
Ectopic Expression ◽  
Tumor Necrosis Factor Receptor ◽  
Null Mutant ◽  
Microbial Infection ◽  
Jnk Pathway

ABSTRACT Two Drosophila tumor necrosis factor receptor-associated factors (TRAF), DTRAF1 and DTRAF2, are proposed to have similar functions with their mammalian counterparts as a signal mediator of cell surface receptors. However, their in vivo functions and related signaling pathways are not fully understood yet. Here, we show that DTRAF1 is an in vivo regulator of c-Jun N-terminal kinase (JNK) pathway in Drosophila melanogaster. Ectopic expression of DTRAF1 in the developing eye induced apoptosis, thereby causing a rough-eye phenotype. Further genetic interaction analyses revealed that the apoptosis in the eye imaginal disc and the abnormal eye morphogenesis induced by DTRAF1 are dependent on JNK and its upstream kinases, Hep and DTAK1. In support of these results, DTRAF1-null mutant showed a remarkable reduction in JNK activity with an impaired development of imaginal discs and a defective formation of photosensory neuron arrays. In contrast, DTRAF2 was demonstrated as an upstream activator of nuclear factor-κB (NF-κB). Ectopic expression of DTRAF2 induced nuclear translocation of two Drosophila NF-κBs, DIF and Relish, consequently activating the transcription of the antimicrobial peptide genes diptericin, diptericin-like protein, and drosomycin. Consistently, the null mutant of DTRAF2 showed immune deficiencies in which NF-κB nuclear translocation and antimicrobial gene transcription against microbial infection were severely impaired. Collectively, our findings demonstrate that DTRAF1 and DTRAF2 play pivotal roles in Drosophila development and innate immunity by differentially regulating the JNK- and the NF-κB-dependent signaling pathway, respectively.

scholarly journals The AF-6 Homolog Canoe Acts as a Rap1 Effector During Dorsal Closure of the Drosophila Embryo

Genetics ◽  
2003 ◽  
Vol 165 (1) ◽  
pp. 159-169
Author(s):  
Benjamin Boettner ◽  
Phoebe Harjes ◽  
Satoshi Ishimaru ◽  
Michael Heke ◽  
Hong Qing Fan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Interaction ◽  
Critical Role ◽  
Adherens Junction ◽  
Small Gtpases ◽  
Drosophila Embryo ◽  
Dorsal Closure ◽  
Cell Sheets ◽  
Jnk Pathway

Abstract Rap1 belongs to the highly conserved Ras subfamily of small GTPases. In Drosophila, Rap1 plays a critical role in many different morphogenetic processes, but the molecular mechanisms executing its function are unknown. Here, we demonstrate that Canoe (Cno), the Drosophila homolog of mammalian junctional protein AF-6, acts as an effector of Rap1 in vivo. Cno binds to the activated form of Rap1 in a yeast two-hybrid assay, the two molecules colocalize to the adherens junction, and they display very similar phenotypes in embryonic dorsal closure (DC), a process that relies on the elongation and migration of epithelial cell sheets. Genetic interaction experiments show that Rap1 and Cno act in the same molecular pathway during DC and that the function of both molecules in DC depends on their ability to interact. We further show that Rap1 acts upstream of Cno, but that Rap1, unlike Cno, is not involved in the stimulation of JNK pathway activity, indicating that Cno has both a Rap1-dependent and a Rap1-independent function in the DC process.

scholarly journals Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ42 and Appl) in Drosophila melanogaster

Biology Open ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. bio049569 ◽  
Author(s):  
Komal Panchal ◽  
Anand Krishna Tiwari
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Genetic Interaction ◽  
Mitochondrial Dynamics ◽  
Ectopic Expression ◽  
Mitochondrial Outer Membrane ◽  
Disease Associated Genes

ABSTRACTMiro (mitochondrial Rho GTPases), a mitochondrial outer membrane protein, facilitates mitochondrial axonal transport along the microtubules to facilitate neuronal function. It plays an important role in regulating mitochondrial dynamics (fusion and fission) and cellular energy generation. Thus, Miro might be associated with the key pathologies of several neurodegenerative diseases (NDs) including Alzheimer's disease (AD). In the present manuscript, we have demonstrated the possible genetic interaction between Miro and AD-related genes such as Tau, Aβ42 and Appl in Drosophila melanogaster. Ectopic expression of Tau, Aβ42 and Appl induced a rough eye phenotype, defects in phototaxis and climbing activity, and shortened lifespan in the flies. In our study, we have observed that overexpression of Miro improves the rough eye phenotype, behavioral activities (climbing and phototaxis) and ATP level in AD model flies. Further, the improvement examined in AD-related phenotypes was correlated with decreased oxidative stress, cell death and neurodegeneration in Miro overexpressing AD model flies. Thus, the obtained results suggested that Miro genetically interacts with AD-related genes in Drosophila and has the potential to be used as a therapeutic target for the design of therapeutic strategies for NDs.This article has an associated First Person interview with the first author of the paper.

scholarly journals miR-11 regulates pupal size of Drosophila melanogaster via directly targeting Ras85D

2017 ◽  
Vol 312 (1) ◽  
pp. C71-C82 ◽  
Author(s):  
Yao Li ◽  
Shengjie Li ◽  
Ping Jin ◽  
Liming Chen ◽  
Fei Ma
Keyword(s):  
Drosophila Melanogaster ◽  
Untranslated Region ◽  
Deletion Mutant ◽  
Ectopic Expression ◽  
Whole Body ◽  
Physiological Processes ◽  
Insulin Producing Cells ◽  
Pupal Size

MicroRNAs play diverse roles in various physiological processes during Drosophila development. In the present study, we reported that miR-11 regulates pupal size during Drosophila metamorphosis via targeting Ras85D with the following evidences: pupal size was increased in the miR-11 deletion mutant; restoration of miR-11 in the miR-11 deletion mutant rescued the increased pupal size phenotype observed in the miR-11 deletion mutant; ectopic expression of miR-11 in brain insulin-producing cells (IPCs) and whole body shows consistent alteration of pupal size; Dilps and Ras85D expressions were negatively regulated by miR-11 in vivo; miR-11 targets Ras85D through directly binding to Ras85D 3′-untranslated region in vitro; removal of one copy of Ras85D in the miR-11 deletion mutant rescued the increased pupal size phenotype observed in the miR-11 deletion mutant. Thus, our current work provides a novel mechanism of pupal size determination by microRNAs during Drosophila melanogaster metamorphosis.

scholarly journals Loss offlflTriggers JNK-Dependent Cell Death inDrosophila

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Jiuhong Huang ◽  
Lei Xue
Keyword(s):  
Cell Death ◽  
Function Analysis ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Dependent Cell ◽  
Jnk Activation ◽  
First Time

falafel(flfl) encodes aDrosophilahomolog of human SMEK whosein vivofunctions remain elusive. In this study, we performed gain-of-function and loss-of-function analysis inDrosophilaand identified flfl as a negative regulator of JNK pathway-mediated cell death. While ectopic expression offlflsuppresses TNF-triggered JNK-dependent cell death, loss offlflpromotes JNK activation and cell death in the developing eye and wing. These data report for the first time an essential physiological function offlflin maintaining tissue homeostasis and organ development. As the JNK signaling pathway has been evolutionary conserved from fly to human, a similar role of PP4R3 in JNK-mediated physiological process is speculated.

Regulation of the chondrocyte phenotype by β-catenin

Development ◽  
2002 ◽  
Vol 129 (23) ◽  
pp. 5541-5550
Author(s):  
Je-Hwang Ryu ◽  
Song-Ja Kim ◽  
Seon-Hee Kim ◽  
Chun-Do Oh ◽  
Sang-Gu Hwang ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Monolayer Culture ◽  
Nuclear Translocation ◽  
Articular Chondrocytes ◽  
Glycogen Synthase ◽  
Ectopic Expression ◽  
Activator Protein 1 ◽  
Chondrocyte Phenotype

β-Catenin regulates important biological processes, including embryonic development and tumorigenesis. We have investigated the role ofβ-catenin in the regulation of the chondrocyte phenotype. Expression ofβ-catenin was high in prechondrogenic mesenchymal cells, but significantly decreased in differentiated chondrocytes both in vivo and in vitro. Accumulation of β-catenin by the inhibition of glycogen synthase kinase-3β with LiCl inhibited chondrogenesis by stabilizing cell-cell adhesion. Conversely, the low level of β-catenin in differentiated articular chondrocytes was increased by post-translational stabilization during phenotypic loss caused by a serial monolayer culture or exposure to retinoic acid or interleukin-1β. Ectopic expression of β-catenin or inhibition of β-catenin degradation with LiCl or proteasome inhibitor caused de-differentiation of chondrocytes. Transcriptional activation ofβ-catenin by its nuclear translocation was sufficient to cause phenotypic loss of differentiated chondrocytes. Expression pattern of Jun, a known target gene of β-catenin, is essentially the same as that of β-catenin both in vivo and in vitro suggesting that Jun and possibly activator protein 1 is involved in the β-catenin regulation of the chondrocyte phenotype.

β2-AR Activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells

2020 ◽  
Author(s):  
Dan Liu ◽  
Xiyue Xu ◽  
Shuci Liu ◽  
Xuan Zhao ◽  
Anqun Tang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Biological Response ◽  
Metastatic Potential ◽  
Adrenergic Signaling ◽  
Signaling Activation

Abstract Background The prolonged hypersecretion of catecholamine induced by chronic stress may correlate with various steps of malignant progression of cancer and β2-AR overexpressed in certain cancer cells may translate the signals from neuroendocrine system to malignant signals by interacting with oncoproteins such as Her2. Crosstalk of the cell signaling pathways mediated by β2-AR and Her2 may promote a stronger or more sustained biological response. However, the molecular mechanisms underlying cross-communication between β2-AR and Her2 mediated signaling pathways are not fully understood. Methods In this study, the effects of adrenergic signaling on Her2 cleavage were evaluated by various assays, such as western blot, immunofluorescence and immunohistochemistry. In order to reveal the mechanism about Her2 cleavage triggered by β2-AR activation, the molecular and pharmacological means were employed. By using in vitro and in vivo assay, the influences of the crosstalk between β2-AR and Her2 on the bio-behaviors of tumor cells were demonstrated. Results Our data demonstrate that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR-199a-5p and SIRT1 and also confirm that catecholamine induction triggers the activities of γ-secretase, leading to shedding of Her2 ECD by ADAM10 and subsequent intramembranous cleavage of Her2 ICD by presenilin-dependent γ-secretase, nuclear translocation of Her2 ICD and enhanced transcription of tumor metastasis-associated gene COX-2 . Chronic stimulation of catecholamine strongly promotes the invasive activities of cancer cells in vitro and spontaneous tumor lung metastasis in mice. Furthermore, the nuclear localization of Her2 was significantly correlated with overexpression of β2-AR in human breast cancer tissues. Conclusion This study illustrates that adrenergic signaling activation triggers Her2 cleavage, resulting in enhanced invasive and metastasis activities of cancer cells. Our data also reveal that an unknown mechanism by which the regulated intramembrane proteolysis (RIP) initiated by β2-AR activation controls a novel Her2-mediated signaling transduction under physiological and pathological conditions.

Phosphorylation-deficient Stat1 inhibits retinoic acid–induced differentiation and cell cycle arrest in U-937 monoblasts

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2870-2878
Author(s):  
Anna Dimberg ◽  
Kenneth Nilsson ◽  
Fredrik Öberg
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Cycle Arrest ◽  
Nuclear Translocation ◽  
Ectopic Expression ◽  
Leukemic Cell ◽  
Potent Inducer ◽  
Cycle Arrest

All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of immature leukemic cell lines in vitro and of acute promyelocytic leukemia (APL) cells in vivo. Recent reports have shown that ATRA induces the expression of several interferon-regulated genes, including signal transducer and activator of transcription (Stat)1. To investigate the role of Stat1 activation in ATRA signaling, sublines were established for the human monoblastic cell line U-937 constitutively expressing wild-type or phosphorylation-defective Stat1, mutated in the conserved tyrosine 701 required for dimerization and nuclear translocation. Results showed that ATRA induction leads to activation of Stat1 by the phosphorylation of tyrosine 701 and subsequent nuclear translocation. Consistent with a functional importance of this activation, ectopic expression of Stat1Y701F suppressed ATRA-induced morphologic differentiation and expression of the monocytic surface markers CD11c and the granulocyte colony-stimulating factor receptor. Moreover, ATRA-induced growth arrest in the G0/G1phase of the cell cycle was inhibited by phosphorylation-deficient Stat1. Taken together, these results indicate that Stat1 is a key mediator of ATRA-induced cell cycle arrest and differentiation of U-937 cells.

Phosphorylation-deficient Stat1 inhibits retinoic acid–induced differentiation and cell cycle arrest in U-937 monoblasts

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2870-2878 ◽  
Author(s):  
Anna Dimberg ◽  
Kenneth Nilsson ◽  
Fredrik Öberg
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Cycle Arrest ◽  
Nuclear Translocation ◽  
Ectopic Expression ◽  
Leukemic Cell ◽  
Potent Inducer ◽  
Cycle Arrest

Abstract All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of immature leukemic cell lines in vitro and of acute promyelocytic leukemia (APL) cells in vivo. Recent reports have shown that ATRA induces the expression of several interferon-regulated genes, including signal transducer and activator of transcription (Stat)1. To investigate the role of Stat1 activation in ATRA signaling, sublines were established for the human monoblastic cell line U-937 constitutively expressing wild-type or phosphorylation-defective Stat1, mutated in the conserved tyrosine 701 required for dimerization and nuclear translocation. Results showed that ATRA induction leads to activation of Stat1 by the phosphorylation of tyrosine 701 and subsequent nuclear translocation. Consistent with a functional importance of this activation, ectopic expression of Stat1Y701F suppressed ATRA-induced morphologic differentiation and expression of the monocytic surface markers CD11c and the granulocyte colony-stimulating factor receptor. Moreover, ATRA-induced growth arrest in the G0/G1phase of the cell cycle was inhibited by phosphorylation-deficient Stat1. Taken together, these results indicate that Stat1 is a key mediator of ATRA-induced cell cycle arrest and differentiation of U-937 cells.

scholarly journals Arginine-Rich Regions Mediate the RNA Binding and Regulatory Activities of the Protein Encoded by the Drosophila melanogaster suppressor of sable Gene

2000 ◽  
Vol 20 (21) ◽  
pp. 8198-8208 ◽  
Author(s):  
Michael A. Turnage ◽  
Paul Brewer-Jensen ◽  
Wen-Li Bai ◽  
Lillie L. Searles
Keyword(s):  
Drosophila Melanogaster ◽  
Rna Binding ◽  
Consensus Sequence ◽  
Polytene Chromosomes ◽  
Ectopic Expression ◽  
Binding Activity ◽  
Suppressor Of Sable ◽  
Rna Accumulation

ABSTRACT The Drosophila melanogaster suppressor of sable gene,su(s), encodes a novel, 150-kDa nuclear RNA binding protein, SU(S), that negatively regulates RNA accumulation from mutant alleles of other genes that have transposon insertions in the 5′ transcribed region. In this study, we delineated the RNA binding domain of SU(S) and evaluated its relevance to SU(S) function in vivo. As a result, we have defined two arginine-rich motifs (ARM1 and ARM2) that mediate the RNA binding activity of SU(S). ARM1 is required for in vitro high-affinity binding of SU(S) to small RNAs that were previously isolated by SELEX (binding site selection assay) and that contain a common consensus sequence. ARM1 is also required for the association of SU(S) with larval polytene chromosomes in vivo. ARM2 promotes binding of SU(S) to SELEX RNAs that lack the consensus sequence and apparently is neither necessary nor sufficient for the stable polytene chromosome association of SU(S). Use of the GAL4/UAS system to drive ectopic expression of su(s) cDNA transgenes revealed two previously unknown properties of SU(S). First, overexpression of SU(S) is lethal. Second, SU(S) negatively regulates expression of su(s)intronless cDNA transgenes, and the ARMs are required for this effect. Considering these and previous results, we propose that SU(S) binds to the 5′ region of nascent transcripts and inhibits RNA production in a manner that can be overcome by splicing complex assembly.

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