The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
Kithiganahalli Narayanaswamy Balaji - One of the best experts on this subject based on the ideXlab platform.
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Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1- and prostaglandin E2-induced regulatory T cell expansion
Scientific Reports, 2016Co-Authors: Sahana Holla, Emmanuel Stephen-victor, Praveen Prakhar, Meenu Sharma, Chaitrali Saha, Vibha Udupa, Srinivas Kaveri, Jagadeesh Bayry, Kithiganahalli Narayanaswamy BalajiAbstract:CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E2 (PGE2) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive Transcription Factor Gli1 directly arbitrated COX-2 Transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.
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Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1-and prostaglandin E 2 -induced regulatory T cell expansion
Scientific Reports, 2016Co-Authors: Sahana Holla, Emmanuel Stephen-victor, Praveen Prakhar, Meenu Sharma, Chaitrali Saha, Vibha Udupa, Srinivas Kaveri, Jagadeesh Bayry, Kithiganahalli Narayanaswamy BalajiAbstract:CD4+CD25+FoxP3+ regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E2 (PGE2) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive Transcription Factor Gli1 directly arbitrated COX-2 Transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.
Andrey G. Zaraisky - One of the best experts on this subject based on the ideXlab platform.
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The cytoskeletal protein Zyxin interacts with the zinc-finger Transcription Factor Zic1 and plays the role of a scaffold for Gli1 and Zic1 interactions during early development of Xenopus laevis.
Biochemical and biophysical research communications, 2018Co-Authors: N. Y. Martynova, Elena A. Parshina, L. V. Ermolina, Andrey G. ZaraiskyAbstract:We have shown recently that the cytoskeletal protein Zyxin participates in the fine tuning of the neural plate pattering in Xenopus laevis embryos by modulating activity of one of the effectors of Hedgehog (Shh) signaling cascade, the Transcription Factor Gli1. In the present work, we show that Zyxin can also interact with the potential modulator of the Shh pathway, the Transcription Factor Zic1. The interaction of proteins occurs primarily by mean of the zinc-finger domain of Zic1 and 2nd LIM domain of Zyxin. Moreover, we have also revealed the ability of the Zyxin, Zic1 and Gli1 to form a ternary complex. The activity of this complex resembles that of the previously described by other authors protein complex formed by Gli1 and Zic1, amplifying effect of the latter. The data obtained provide evidence for the scaffolding role of Zyxin for Gli1 and Zic1 interactions and confirm its role in the regulation of Shh signaling cascade.
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The cytoskeletal protein Zyxin inhibits Shh signaling during the CNS patterning in Xenopus laevis through interaction with the Transcription Factor Gli1.
Developmental biology, 2013Co-Authors: N. Y. Martynova, Fedor M. Eroshkin, Fatima K. Gyoeva, L. V. Ermolina, Galina V. Ermakova, Natalia S. Baturina, Andrey G. ZaraiskyAbstract:Zyxin is a cytoskeletal protein that controls cell movements by regulating actin filaments assembly, but it can also modulate gene expression owing to its interactions with the proteins involved in signaling cascades. Therefore, identification of proteins that interact with Zyxin in embryonic cells is a promising way to unravel mechanisms responsible for coupling of two major components of embryogenesis: morphogenetic movements and cell differentiation. Now we show that in Xenopus laevis embryos Zyxin can bind to and suppress activity of the primary effector of Sonic hedgehog (Shh) signaling cascade, the Transcription Factor Gli1. By using loss- and gain-of-function approaches, we demonstrate that Zyxin is essential for reduction of Shh signaling within the dorsal part of the neural tube of X. laevis embryo. Thus, our finding discloses a novel function of Zyxin in fine tuning of the central neural system patterning which is based on the ventral-to-dorsal gradient of Shh signaling.
Maite G Fernandezbarrena - One of the best experts on this subject based on the ideXlab platform.
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the Transcription Factor Gli1 modulates the inflammatory response during pancreatic tissue remodeling
Journal of Biological Chemistry, 2014Co-Authors: Esha Mathew, Maite G Fernandezbarrena, Martin E Fernandezzapico, Meredith A Collins, Alexander M Holtz, Wei Yan, James O Hogan, Zachary Tata, Benjamin L Allen, Marina Pasca Di MaglianoAbstract:Pancreatic cancer, one of the deadliest human malignancies, is almost uniformly associated with a mutant, constitutively active form of the oncogene Kras. Studies in genetically engineered mouse models have defined a requirement for oncogenic KRAS in both the formation of pancreatic intraepithelial neoplasias, the most common precursor lesions to pancreatic cancer, and in the maintenance and progression of these lesions. Previous work using an inducible model allowing tissue-specific and reversible expression of oncogenic Kras in the pancreas indicates that inactivation of this GTPase at the pancreatic intraepithelial neoplasia stage promotes pancreatic tissue repair. Here, we extend these findings to identify Gli1, a Transcriptional effector of the Hedgehog pathway, as a central player in pancreatic tissue repair upon Kras inactivation. Deletion of a single allele of Gli1 results in improper stromal remodeling and perdurance of the inflammatory infiltrate characteristic of pancreatic tumorigenesis. Strikingly, this partial loss of Gli1 affects activated fibroblasts in the pancreas and the recruitment of immune cells that are vital for tissue recovery. Analysis of the mechanism using expression and chromatin immunoprecipitation assays identified a subset of cytokines, including IL-6, mIL-8, Mcp-1, and M-csf (Csf1), as direct Gli1 target genes potentially mediating this phenomenon. Finally, we demonstrate that canonical Hedgehog signaling, a known regulator of Gli1 activity, is required for pancreas recovery. Collectively, these data delineate a new pathway controlling tissue repair and highlight the importance of Gli1 in regulation of the pancreatic microenvironment during this cellular process.
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identification of novel non coding rna based negative feedback regulating the expression of the oncogenic Transcription Factor Gli1
Molecular Oncology, 2014Co-Authors: Mohammed Ferdous-ur Rahman, Yumei Diao, Eleni A Liapi, Enikö Sonkoly, Mona Stahle, Andor Pivarcsi, Victoria Eugenia Villegas, Maite G Fernandezbarrena, Laura AnnaratoneAbstract:Non-coding RNAs are a complex class of nucleic acids, with growing evidence supporting regulatory roles in gene expression. Here we identify a non-coding RNA located head-to-head with the gene encoding the Glioma-associated oncogene 1 (Gli1), a Transcriptional effector of multiple cancer-associated signaling pathways. The expression of this three-exon Gli1 antisense (Gli1AS) RNA in cancer cells was concordant with Gli1 levels. siRNAs knockdown of Gli1AS up-regulated Gli1 and increased cellular proliferation and tumor growth in a xenograft model system. Conversely, Gli1AS overexpression decreased the levels of Gli1, its target genes PTCH1 and PTCH2, and cellular proliferation. Additionally, we demonstrate that Gli1 knockdown reduced Gli1AS, while Gli1 overexpression increased Gli1AS, supporting the role of Gli1AS as a target gene of the Gli1 Transcription Factor. Activation of TGFβ and Hedgehog signaling, two known regulators of Gli1 expression, conferred a concordant up-regulation of Gli1 and Gli1AS in cancer cells. Finally, analysis of the mechanism underlying the interplay between Gli1 and Gli1AS indicates that the non-coding RNA elicits a local alteration of chromatin structure by increasing the silencing mark H3K27me3 and decreasing the recruitment of RNA polymerase II to this locus. Taken together, the data demonstrate the existence of a novel non-coding RNA-based negative feedback loop controlling Gli1 levels, thus expanding the repertoire of mechanisms regulating the expression of this oncogenic Transcription Factor.
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inactivation of the Transcription Factor Gli1 accelerates pancreatic cancer progression
Journal of Biological Chemistry, 2014Co-Authors: Lisa D Mills, Maite G Fernandezbarrena, Ronald J Marler, Lizhi Zhang, Phyllis A Svingen, Maneesh Dave, William R Bamlet, Robert R Mcwilliams, Gloria M Petersen, William A FaubionAbstract:The role of Gli1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the Gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, Gli1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of Gli1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of Gli1 by TUNEL staining. Together, these findings define a novel pathway regulated by Gli1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting Gli1-related pathways.
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the Transcription Factor Gli1 interacts with smad proteins to modulate transforming growth Factor β induced gene expression in a p300 creb binding protein associated Factor pcaf dependent manner
Journal of Biological Chemistry, 2014Co-Authors: Monica D Nye, Luciana L Almada, Maite G Fernandezbarrena, David L Marks, Sherine F Elsawa, Anne M Vrabel, Ezequiel J Tolosa, Volker Ellenrieder, Martin E FernandezzapicoAbstract:The biological role of the Transcription Factor Gli1 in the regulation of tumor growth is well established; however, the molecular events modulating this phenomenon remain elusive. Here, we demonstrate a novel mechanism underlying the role of Gli1 as an effector of TGFβ signaling in the regulation of gene expression in cancer cells. TGFβ stimulates Gli1 activity in cancer cells and requires its Transcriptional activity to induce BCL2 expression. Analysis of the mechanism regulating this interplay identified a new Transcriptional complex including Gli1 and the TGFβ-regulated Transcription Factor, SMAD4. We demonstrate that SMAD4 physically interacts with Gli1 for concerted regulation of gene expression and cellular survival. Activation of the TGFβ pathway induces Gli1-SMAD4 complex binding to the BCL2 promoter whereas disruption of the complex through SMAD4 RNAi depletion impairs Gli1-mediated Transcription of BCL2 and cellular survival. Further characterization demonstrated that SMAD2 and the histone acetyltransferase, PCAF, participate in this regulatory mechanism. Both proteins bind to the BCL2 promoter and are required for TGFβ- and Gli1-stimulated gene expression. Moreover, SMAD2/4 RNAi experiments showed that these Factors are required for the recruitment of Gli1 to the BCL2 promoter. Finally, we determined whether this novel Gli1 Transcriptional pathway could regulate other TGFβ targets. We found that two additional TGFβ-stimulated genes, INTERLEUKIN-7 and CYCLIN D1, are dependent upon the intact Gli1-SMAD-PCAF complex for Transcriptional activation. Collectively, these results define a novel epigenetic mechanism that uses the Transcription Factor Gli1 and its associated complex as a central effector to regulate gene expression in cancer cells.
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activation of the Transcription Factor Gli1 by wnt signaling underlies the role of sulfatase 2 as a regulator of tissue regeneration
Journal of Biological Chemistry, 2013Co-Authors: Ikuo Nakamura, Luciana L Almada, Maite G Fernandezbarrena, Sherine F Elsawa, Lisa D Mills, Maria C Ortizruiz, Paola Romecin, Kadra H Gulaid, Catherine D Moser, Jing Jing HanAbstract:Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-Gli1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth Factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced β-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the Transcription Factor Gli1 as a novel target of the SULF2-WNT cascade. WNT induces Gli1 expression in a SULF2- and β-CATENIN-dependent manner. Gli1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a Gli1 Transcriptional target. Gli1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring Gli1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-Gli1-CYCLIN D1 pathway.
Sahana Holla - One of the best experts on this subject based on the ideXlab platform.
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Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1- and prostaglandin E2-induced regulatory T cell expansion
Scientific Reports, 2016Co-Authors: Sahana Holla, Emmanuel Stephen-victor, Praveen Prakhar, Meenu Sharma, Chaitrali Saha, Vibha Udupa, Srinivas Kaveri, Jagadeesh Bayry, Kithiganahalli Narayanaswamy BalajiAbstract:CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E2 (PGE2) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive Transcription Factor Gli1 directly arbitrated COX-2 Transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.
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Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1-and prostaglandin E 2 -induced regulatory T cell expansion
Scientific Reports, 2016Co-Authors: Sahana Holla, Emmanuel Stephen-victor, Praveen Prakhar, Meenu Sharma, Chaitrali Saha, Vibha Udupa, Srinivas Kaveri, Jagadeesh Bayry, Kithiganahalli Narayanaswamy BalajiAbstract:CD4+CD25+FoxP3+ regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E2 (PGE2) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive Transcription Factor Gli1 directly arbitrated COX-2 Transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.
N. Y. Martynova - One of the best experts on this subject based on the ideXlab platform.
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The cytoskeletal protein Zyxin interacts with the zinc-finger Transcription Factor Zic1 and plays the role of a scaffold for Gli1 and Zic1 interactions during early development of Xenopus laevis.
Biochemical and biophysical research communications, 2018Co-Authors: N. Y. Martynova, Elena A. Parshina, L. V. Ermolina, Andrey G. ZaraiskyAbstract:We have shown recently that the cytoskeletal protein Zyxin participates in the fine tuning of the neural plate pattering in Xenopus laevis embryos by modulating activity of one of the effectors of Hedgehog (Shh) signaling cascade, the Transcription Factor Gli1. In the present work, we show that Zyxin can also interact with the potential modulator of the Shh pathway, the Transcription Factor Zic1. The interaction of proteins occurs primarily by mean of the zinc-finger domain of Zic1 and 2nd LIM domain of Zyxin. Moreover, we have also revealed the ability of the Zyxin, Zic1 and Gli1 to form a ternary complex. The activity of this complex resembles that of the previously described by other authors protein complex formed by Gli1 and Zic1, amplifying effect of the latter. The data obtained provide evidence for the scaffolding role of Zyxin for Gli1 and Zic1 interactions and confirm its role in the regulation of Shh signaling cascade.
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The cytoskeletal protein Zyxin inhibits Shh signaling during the CNS patterning in Xenopus laevis through interaction with the Transcription Factor Gli1.
Developmental biology, 2013Co-Authors: N. Y. Martynova, Fedor M. Eroshkin, Fatima K. Gyoeva, L. V. Ermolina, Galina V. Ermakova, Natalia S. Baturina, Andrey G. ZaraiskyAbstract:Zyxin is a cytoskeletal protein that controls cell movements by regulating actin filaments assembly, but it can also modulate gene expression owing to its interactions with the proteins involved in signaling cascades. Therefore, identification of proteins that interact with Zyxin in embryonic cells is a promising way to unravel mechanisms responsible for coupling of two major components of embryogenesis: morphogenetic movements and cell differentiation. Now we show that in Xenopus laevis embryos Zyxin can bind to and suppress activity of the primary effector of Sonic hedgehog (Shh) signaling cascade, the Transcription Factor Gli1. By using loss- and gain-of-function approaches, we demonstrate that Zyxin is essential for reduction of Shh signaling within the dorsal part of the neural tube of X. laevis embryo. Thus, our finding discloses a novel function of Zyxin in fine tuning of the central neural system patterning which is based on the ventral-to-dorsal gradient of Shh signaling.