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‣ Signal transduction in Plasmodium-Red Blood Cells interactions and in cytoadherence

Cruz, Laura Nogueira da; Wu, Yang; Craig, Alister G.; Garcia, Celia Regina da Silva
Fonte: Academia Brasileira de Ciências Publicador: Academia Brasileira de Ciências
Tipo: Artigo de Revista Científica
Português
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Malaria is responsible for more than 1.5 million deaths each year, especially among children (Snow et al. 2005). Despite of the severity of malaria situation and great effort to the development of new drug targets (Yuan et al. 2011) there is still a relative low investment toward antimalarial drugs. Briefly there are targets classes of antimalarial drugs currently being tested including: kinases, proteases, ion channel of GPCR, nuclear receptor, among others (Gamo et al. 2010). Here we review malaria signal transduction pathways in Red Blood Cells (RBC) as well as infected RBCs and endothelial cells interactions, namely cytoadherence. The last process is thought to play an important role in the pathogenesis of severe malaria. The molecules displayed on the surface of both infected erythrocytes (IE) and vascular endothelial cells (EC) exert themselves as important mediators in cytoadherence, in that they not only induce structural and metabolic changes on both sides, but also trigger multiple signal transduction processes, leading to alteration of gene expression, with the balance between positive and negative regulation determining endothelial pathology during a malaria infection.

‣ Transcription profiling of signal transduction-related genes in sugarcane tissues

Papini-Terzi, F. S.; Rocha, F. R.; Vencio, RZN; Oliveira, K. C.; Felix, J. D.; Vicentini, R.; Rocha, C. D.; Simoes, ACQ; Ulian, E. C.; Di Mauro, SMZ; Da Silva, A. M.; Pereira, CAD; Menossi, M.; Souza, G. M.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica Formato: 27-38
Português
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A collection of 237,954 sugarcane ESTs was examined in search of signal transduction genes. Over 3,500 components involved in several aspects of signal transduction, transcription, development, cell cycle, stress responses and pathogen interaction were compiled into the Sugarcane Signal Transduction (SUCAST) Catalogue. Sequence comparisons and protein domain analysis revealed 477 receptors, 510 protein kinases, 107 protein phosphatases, 75 small GTPases, 17 G-proteins, 114 calcium and inositol metabolism proteins, and over 600 transcription factors. The elements were distributed into 29 main categories subdivided into 409 sub-categories. Genes with no matches in the public databases and of unknown function were also catalogued. A cDNA microarray was constructed to profile individual variation of plants cultivated in the field and transcript abundance in six plant organs (flowers, roots, leaves, lateral buds, and 1(st) and 4(th) internodes). From 1280 distinct elements analyzed, 217 (17%) presented differential expression in two biological samples of at least one of the tissues tested. A total of 153 genes (12%) presented highly similar expression levels in all tissues. A virtual profile matrix was constructed and the expression profiles were validated by real-time PCR. The expression data presented can aid in assigning function for the sugarcane genes and be useful for promoter characterization of this and other economically important grasses.

‣ Efeito do doador de oxido nitrico S-Nitroso-acetilcisteina sobre a sobre a sinalização celular da angiotensina II em coração e cardiomiocitos de ratos; Effect of the nitric oxide donor S-Nitroso-N-Acetylcysteine on angiotensin II signal transduction in heart and cardiomyocites of rats

Fernando Ganzarolli de Oliveira
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 31/08/2005 Português
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Angiotensina II (AngII) desempenha um papel importante na gênese da hipertrofia miocárdica. Grande parte do estímulo hipertrófico determinado pela AngII depende da ativação de sinalização intracelular envolvendo membros das famílias de transdutores de sinais mitogen-activated-protein kinase (MAPK) e Janus Kinase (JAK)/ signal transducer and activator of transcription (STAT). Agentes farmacológicos doadores de óxido nítrico (NO) estão sendo objeto de intensa pesquisa, atualmente, pelo seu potencial terapêutico em condições clínicas envolvidas na hipertrofia miocárdica. No presente trabalho, avaliamos a propriedade do S-nitroso-acetilcisteína (SNAC) de modular a transdução de sinal da AngII mediada por membros da família das MAPK e JAK/STAT em coração e cardiomiócitos isolados de ratos. SNAC foi capaz de reverter significativamente a ativação promovida pela AngII na via de sinalização JAK2/STAT1 e 3 em coração e cardiomiócitos. Além disso, SNAC reverteu a ativação por AngII em cJun-N-terminal Kinase (JNK)1/2/3. Entretanto, SNAC acentuou o efeito da AngII em Extracellular Regulated Kinase (ERK) 1 e 2. Finalmente, nem AngII nem SNAC exerceram qualquer efeito sobre p38MAPK. Como resultado, houve menor expressão dos immediate early genes c-jun e c-fos...

‣ Signal transduction in Plasmodium-Red Blood Cells interactions and in cytoadherence

Cruz,Laura N.; Wu,Yang; Craig,Alister G.; Garcia,Célia R.S.
Fonte: Academia Brasileira de Ciências Publicador: Academia Brasileira de Ciências
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2012 Português
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Malaria is responsible for more than 1.5 million deaths each year, especially among children (Snow et al. 2005). Despite of the severity of malaria situation and great effort to the development of new drug targets (Yuan et al. 2011) there is still a relative low investment toward antimalarial drugs. Briefly there are targets classes of antimalarial drugs currently being tested including: kinases, proteases, ion channel of GPCR, nuclear receptor, among others (Gamo et al. 2010). Here we review malaria signal transduction pathways in Red Blood Cells (RBC) as well as infected RBCs and endothelial cells interactions, namely cytoadherence. The last process is thought to play an important role in the pathogenesis of severe malaria. The molecules displayed on the surface of both infected erythrocytes (IE) and vascular endothelial cells (EC) exert themselves as important mediators in cytoadherence, in that they not only induce structural and metabolic changes on both sides, but also trigger multiple signal transduction processes, leading to alteration of gene expression, with the balance between positive and negative regulation determining endothelial pathology during a malaria infection.

‣ Domain Interactions on the ntr Signal Transduction Pathway: Two-Hybrid Analysis of Mutant and Truncated Derivatives of Histidine Kinase NtrB

Martínez-Argudo, Isabel; Salinas, Paloma; Maldonado, Rafael; Contreras, Asunción
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2002 Português
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We have used the yeast two-hybrid system to analyze protein-protein interactions mediated by domains of regulatory proteins of the ntr signal transduction system, including interactions among NtrB derivatives and their interactions with NtrC and PII from Klebsiella pneumoniae. Interactions took place only between proteins or protein domains belonging to the ntr signal transduction system and not between proteins or domains from noncognate regulators. NtrB and its transmitter domain, but not NtrC, CheA, or the cytoplasmic C terminus of EnvZ, interacted with PII. In addition, interaction of NtrB with NtrC, but not with PII, depended on the histidine phosphotransfer domain. Point mutation A129T, diminishing the NtrC phosphatase activity of NtrB, affected the strength of the signals between NtrC and the transmitter module of NtrB but had no impact on PII signals, suggesting that A129T prevents the conformational change needed by NtrB to function as a phosphatase for NtrC, rather than disturbing binding to PII.

‣ A Bacterial Signal Transduction System Controls Genetic Exchange and Motility

Lang, Andrew S.; Beatty, J. Thomas
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /02/2002 Português
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The bacterium Rhodobacter capsulatus is capable of an unusual form of genetic exchange, mediated by a transducing bacteriophage-like particle called the gene transfer agent (GTA). GTA production by R. capsulatus is controlled at the level of transcription by a cellular two-component signal transduction system that includes a putative histidine kinase (CckA) and response regulator (CtrA). We found that, in addition to regulating genetic exchange by R. capsulatus, this signal transduction system controls motility. As with the regulation of GTA production, the control of motility by CckA and CtrA occurs through modulation of gene transcription. Disruptions of the cckA and ctrA genes resulted in a loss of class II, class III, and class IV flagellar gene transcripts, suggesting that cckA and ctrA function in motility as class I flagellar genes. We also found that, analogous to the GTA genes, transcription of R. capsulatus flagellar genes appears to be growth phase dependent: class II flagellar gene transcripts are maximal in the mid-log phase of the culture growth cycle, whereas class III gene transcripts are maximal in the late-log phase of growth. We speculate that coordinate regulation of motility and GTA-mediated genetic exchange in R. capsulatus exists because these two processes are complementary mechanisms for cells to cope with unfavorable conditions in natural environments.

‣ The ARG1-LIKE2 Gene of Arabidopsis Functions in a Gravity Signal Transduction Pathway That Is Genetically Distinct from the PGM Pathway1

Guan, Changhui; Rosen, Elizabeth S.; Boonsirichai, Kanokporn; Poff, Kenneth L.; Masson, Patrick H.
Fonte: The American Society for Plant Biologists Publicador: The American Society for Plant Biologists
Tipo: Artigo de Revista Científica
Publicado em /09/2003 Português
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The arl2 mutants of Arabidopsis display altered root and hypocotyl gravitropism, whereas their inflorescence stems are fully gravitropic. Interestingly, mutant roots respond like the wild type to phytohormones and an inhibitor of polar auxin transport. Also, their cap columella cells accumulate starch similarly to wild-type cells, and mutant hypocotyls display strong phototropic responses to lateral light stimulation. The ARL2 gene encodes a DnaJ-like protein similar to ARG1, another protein previously implicated in gravity signal transduction in Arabidopsis seedlings. ARL2 is expressed at low levels in all organs of seedlings and plants. arl2-1 arg1-2 double mutant roots display kinetics of gravitropism similar to those of single mutants. However, double mutants carrying both arl2-1 and pgm-1 (a mutation in the starch-biosynthetic gene PHOSPHOGLUCOMUTASE) at the homozygous state display a more pronounced root gravitropic defect than the single mutants. On the other hand, seedlings with a null mutation in ARL1, a paralog of ARG1 and ARL2, behave similarly to the wild type in gravitropism and other related assays. Taken together, the results suggest that ARG1 and ARL2 function in the same gravity signal transduction pathway in the hypocotyl and root of Arabidopsis seedlings...

‣ Signal Transduction Cascade between EvgA/EvgS and PhoP/PhoQ Two-Component Systems of Escherichia coli

Eguchi, Yoko; Okada, Tadashi; Minagawa, Shu; Oshima, Taku; Mori, Hirotada; Yamamoto, Kaneyoshi; Ishihama, Akira; Utsumi, Ryutaro
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2004 Português
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Transcriptional analysis of a constitutively active mutant of the EvgA/EvgS two-component system of Escherichia coli resulted in enhanced expression of 13 PhoP/PhoQ-regulated genes, crcA, hemL, mgtA, ompT, phoP, phoQ, proP, rstA, rstB, slyB, ybjG, yrbL, and mgrB. This regulatory network between the two systems also occurred as a result of overproduction of the EvgA regulator; however, enhanced transcription of the phoPQ genes did not further activate expression of the PhoP/PhoQ-regulated genes. These results demonstrated signal transduction from the EvgA/EvgS system to the PhoP/PhoQ system in E. coli and also identified the genes that required the two systems for enhanced expression. This is one example of the intricate signal transduction networks that are posited to exist in E. coli.

‣ Genetic Characterization of a Multicomponent Signal Transduction System Controlling the Expression of Cable Pili in Burkholderia cenocepacia

Tomich, Mladen; Mohr, Christian D.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/2004 Português
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Cable pili are peritrichous organelles expressed by certain strains of Burkholderia cenocepacia, believed to facilitate colonization of the lower respiratory tract in cystic fibrosis patients. The B. cenocepacia cblBACDS operon encodes the structural and accessory proteins required for the assembly of cable pili, as well as a gene designated cblS, predicted to encode a hybrid sensor kinase protein of bacterial two-component signal transduction systems. In this study we report the identification of two additional genes, designated cblT and cblR, predicted to encode a second hybrid sensor kinase and a response regulator, respectively. Analyses of the deduced amino acid sequences of the cblS and cblT gene products revealed that both putative sensor kinases have transmitter and receiver domains and that the cblT gene product has an additional C-terminal HPt domain. Mutagenesis of the cblS, cblT, or cblR gene led to a block in expression of CblA, the major pilin subunit, and a severe decrease in cblA transcript abundance. Using transcriptional fusion analyses, the decrease in the abundance of the cblA transcript in the cblS, cblT, and cblR mutants was shown to be due to a block in transcription from the cblB-proximal promoter, located upstream of the cblBACDS operon. Furthermore...

‣ TRAF6 Is Required for TRAF2-Dependent CD40 Signal Transduction in Nonhemopoietic Cells†

Davies, Clare C.; Mak, Tak W.; Young, Lawrence S.; Eliopoulos, Aristides G.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2005 Português
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The emerging role of CD40, a tumor necrosis factor (TNF) receptor family member, in immune regulation, disease pathogenesis, and cancer therapy necessitates the analysis of CD40 signal transduction in a wide range of tissue types. In this study we present evidence that the CD40-interacting proteins TRAF2 and TRAF6 play an important physiological role in CD40 signaling in nonhemopoietic cells. Using mutational analysis of the CD40 cytoplasmic tail, we demonstrate that the specific binding of TRAF2 to CD40 is required for efficient signaling on the NF-κB, Jun N-terminal protein kinase (JNK), and p38 axis. In fibroblasts lacking TRAF2 or in carcinoma cells in which TRAF2 has been depleted by RNA interference, the CD40-mediated activation of NF-κB and JNK is significantly reduced, and the activation of p38 and Akt is severely impaired. Interestingly, whereas the TRAF6-interacting membrane-proximal domain of CD40 has a minor role in signal transduction, studies utilizing TRAF6 knockout fibroblasts and RNA interference in epithelial cells reveal that the CD40-induced activation of NF-κB, JNK, p38, and Akt requires the integrity of TRAF6. Furthermore, we provide evidence that TRAF6 regulates CD40 signal transduction not only through its direct binding to CD40 but also indirectly via its association with TRAF2. These observations provide novel insight into the mechanisms of CD40 signaling and the multiple roles played by TRAF6 in signal transduction.

‣ Signal Integration by the Two-Component Signal Transduction Response Regulator CpxR▿

Wolfe, Alan J.; Parikh, Niyati; Lima, Bruno P.; Zemaitaitis, Bozena
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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The CpxAR two-component signal transduction system in Escherichia coli and other pathogens senses diverse envelope stresses and promotes the transcription of a variety of genes that remedy these stresses. An important member of the CpxAR regulon is cpxP. The CpxA-dependent transcription of cpxP has been linked to stresses such as misfolded proteins and alkaline pH. It also has been proposed that acetyl phosphate, the intermediate of the phosphotransacetylase (Pta)-acetate kinase (AckA) pathway, can activate the transcription of cpxP in a CpxA-independent manner by donating its phosphoryl group to CpxR. We tested this hypothesis by measuring the transcription of cpxP using mutants with mutations in the CpxAR pathway, mutants with mutations in the Pta-AckA pathway, and mutants with a combination of both types of mutations. From this epistasis analysis, we learned that CpxR integrates diverse stimuli. The stimuli that originate in the envelope depend on CpxA, while those associated with growth and central metabolism depend on the Pta-AckA pathway. While CpxR could receive a phosphoryl group from acetyl phosphate, this global signal was not the primary trigger for CpxR activation associated with the Pta-AckA pathway. On the strength of these results...

‣ p66shc Negatively Regulates Insulin-Like Growth Factor I Signal Transduction via Inhibition of p52shc Binding to Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Leading to Impaired Growth Factor Receptor-Bound Protein-2 Membrane Recruitment

Xi, Gang; Shen, Xinchun; Clemmons, David R.
Fonte: The Endocrine Society Publicador: The Endocrine Society
Tipo: Artigo de Revista Científica
Publicado em /09/2008 Português
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Our previous studies have indicated an essential role of p52shc in mediating IGF-I activation of MAPK in smooth muscle cells (SMC). However, the role of the p66 isoform of shc in IGF-I signal transduction is unclear. In the current study, two approaches were employed to investigate the role of p66shc in mediating IGF-I signaling. Knockdown p66shc by small interfering RNA enhanced IGF-I-stimulated p52shc tyrosine phosphorylation and growth factor receptor-bound protein-2 (Grb2) association, resulting in increased IGF-I-dependent MAPK activation. This was associated with enhanced IGF-I-stimulated cell proliferation. In contrast, knockdown of p66shc did not affect IGF-I-stimulated IGF-I receptor tyrosine phosphorylation. Overexpression of p66shc impaired IGF-I-stimulated p52shc tyrosine phosphorylation and p52shc-Grb2 association. In addition, IGF-I-dependent MAPK activation was also impaired, and SMC proliferation in response to IGF-I was inhibited. IGF-I-dependent cell migration was enhanced by p66shc knockdown and attenuated by p66shc overexpression. Mechanistic studies indicated that p66shc inhibited IGF-I signal transduction via competitively inhibiting the binding of Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) to SHP substrate-1 (SHPS-1)...

‣ Restoration of γ-Sarcoglycan Localization and Mechanical Signal Transduction Are Independent in Murine Skeletal Muscle*

Barton, Elisabeth R.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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Limb girdle muscular dystrophy 2C is caused by mutations in the γ-sarcoglycan gene (gsg) that results in loss of this protein, and disruption of the sarcoglycan (SG) complex. Signal transduction after mechanical perturbation is mediated, in part, through the SG complex and leads to phosphorylation of tyrosines on the intracellular portions of the sarcoglycans. This study tested if the Tyr6 in the intracellular region of γ-sarcoglycan protein (γ-SG) was necessary for proper localization of the protein in skeletal muscle membranes or for the normal pattern of ERK1/2 phosphorylation after eccentric contractions. Viral mediated gene transfer of wild type gsg (WTgsg) and mutant gsg lacking Tyr6 (Y6Agsg) was performed into the muscles of gsg−/− mice. Muscles were examined for production and stability of the γ-SG, as well as the level of ERK1/2 phosphorylation before and after eccentric contraction. Sarcolemmal localization of γ-SG was achieved regardless of which construct was expressed. However, only expression of WTgsg corrected the aberrant ERK1/2 phosphorylation associated with the absence of γ-SG, whereas Y6Agsg failed to have any effect. This study shows that localization of γ-SG does not require Tyr6, but localization alone is insufficient for restoration of normal signal transduction patterns after mechanical perturbation.

‣ From Molecular Details of the Interplay between Transmembrane Helices of the Thyrotropin Receptor to General Aspects of Signal Transduction in Family A G-protein-coupled Receptors (GPCRs)*

Kleinau, Gunnar; Hoyer, Inna; Kreuchwig, Annika; Haas, Ann-Karin; Rutz, Claudia; Furkert, Jens; Worth, Catherine L.; Krause, Gerd; Schülein, Ralf
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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Transmembrane helices (TMHs) 5 and 6 are known to be important for signal transduction by G-protein-coupled receptors (GPCRs). Our aim was to characterize the interface between TMH5 and TMH6 of the thyrotropin receptor (TSHR) to gain molecular insights into aspects of signal transduction and regulation. A proline at TMH5 position 5.50 is highly conserved in family A GPCRs and causes a twist in the helix structure. Mutation of the TSHR-specific alanine (Ala-5935.50) at this position to proline resulted in a 20-fold reduction of cell surface expression. This indicates that TMH5 in the TSHR might have a conformation different from most other family A GPCRs by forming a regular α-helix. Furthermore, linking our own and previous data from directed mutagenesis with structural information led to suggestions of distinct pairs of interacting residues between TMH5 and TMH6 that are responsible for stabilizing either the basal or the active state. Our insights suggest that the inactive state conformation is constrained by a core set of polar interactions among TMHs 2, 3, 6, and 7 and in contrast that the active state conformation is stabilized mainly by non-polar interactions between TMHs 5 and 6. Our findings might be relevant for all family A GPCRs as supported by a statistical analysis of residue properties between the TMHs of a vast number of GPCR sequences.

‣ The two-component signal transduction system RR06/HK06 regulates expression of cbpA in Streptococcus pneumonia

Standish, A.; Stroeher, U.; Paton, J.
Fonte: Natl Acad Sciences Publicador: Natl Acad Sciences
Tipo: Artigo de Revista Científica
Publicado em //2005 Português
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Streptococcus pneumoniae encounters a number of environmental niches in the body, including the nasopharynx, lungs, blood, middle ear, and brain. Recent studies have identified 13 putative two-component signal-transduction systems in S. pneumoniae, which are likely to be important for gene regulation in response to external stimuli. Here, we present conclusive evidence for the regulation of choline binding protein A (CbpA), a major pneumococcal virulence factor and protective antigen, by one of these two-component signal-transduction systems. We have demonstrated divergent expression of cbpA in unmarked hk06 and rr06 deletion mutants relative to wild-type S. pneumoniae D39 by using Western immunoblotting and real-time RT-PCR. Electrophoretic mobility-shift and solid-phase binding assays have demonstrated the binding of RR06 to the promoter region of cbpA, suggesting that RR06/HK06 directly regulates cbpA transcription. We have also shown that this system is important for the ability of the pneumococcus to adhere to epithelial cells in vitro and to survive and proliferate in an in vivo mouse model. Thus, the RR06/HK06 system has a significant role in pathogenesis, both in colonization and invasive disease.; Alistair J. Standish, Uwe H. Stroeher...

‣ Parallel and miniaturised Analysis of Protein-Protein Interactions in T-Cell Signal Transduction by Fluorescence Cross-Correlation Spectroscopy and Peptide Microarrays; Parallele und miniaturisierte Analyse von Protein-Protein-Interaktionen in der T-Zell-Signaltransduktion mittels Fluoreszenz-Kreuzkorrelations-Spektroskopie und Peptidmikroarrays

Stoevesandt, Oda
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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The aim of this thesis was to develop methods for the parallel analysis of complexes of endogenous proteins in T-cell signal transduction. We opted for detection in cell lysates, as the labelling of proteins in lysates is more versatile and more amenable to parallelisation compared to the labelling of proteins in life cells. Two approaches were developed, based on peptide microarrays and on fluorescence correlation and cross correlation spectroscopy (FCS / FCCS). It is shown that peptide microarrays provide a robust and quantitative means for detecting signalling-dependent changes of protein interactions. Recruitment of a protein into a complex leads to the masking of an otherwise exposed binding site. In cell lysates this masking can be detected by reduced binding to a microarray carrying a peptide corresponding to the binding motif of the respective interaction domain. This approach provides a significant shortcut to the detection of molecular interactions. It was first exemplified for the binding of ZAP70 to a bis-pY-motif of the activated T-cell receptor via its tandem SH2 domain. The activation-dependent recruitment of ZAP70 into signalling complexes reduced the microarray-bound signal, providing quantitative information on the change of the fraction of available binding sites. The concept was extended with microarrays comprising 24 peptides representing binding motifs for SH2...

‣ Novel structures of PII signal transduction proteins from oxygenic phototropic organisms

Chellamuthu, Vasuki Ranjani
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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PII proteins constitute one of the most widely distributed families of signal transduction proteins, whose representatives are present in archaea, bacteria and plants. They play a pivotal role to control the nitrogen, carbon and energy status of the cell in response to the central metabolites ATP, ADP and 2-oxoglutarate (2-OG). These signals from central metabolites are integrated by PII proteins and transmitted to the regulatory targets (protein modifying enzymes, metabolic enzymes, transporters and transcription factors). In oxygenic phototrophic organisms, from cyanobacteria to higher plants, the controlling enzyme of arginine synthesis, N-acetyl-L-glutamate kinase (NAGK) is a major PII target, whose activity responds to the cellular metabolites via PII signalling. In this work, novel crystal structures of PII signal transduction proteins from oxygenic phototrophs (Synechococcus elongatus and Chlamydomonas reinhardtii) in the presence of signalling metabolites and in complex with NAGK are reported. These structures give deeper insights into PII-mediated mechanism and regulation which are in accordance with the obtained biochemical data. The novel role of glutamine as a signalling molecule in C. reinhardtii is elucidated for the first time...

‣ Signal Transduction in tandem HAMP domains

Natarajan, Janani
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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The incidence of HAMP tandems in bacterial signaling proteins is low and presently it is unknown what physiological advantage may be gained by using a tandem. Presently a simple general mechanism of HAMP signaling which satisfactorily accounts for all experimental data cannot be presented. To study signal transduction via HAMP domains we used an in vitro biochemical system in which the signal output is affected exclusively by the HAMP domain that is inserted between the Tsr receptor as the input and the Rv3645 adenylyl cyclase as output domain. Initially neither the HAMP tandem nor its respective monomers operated as signal transducers in our system. The introduction of five targeted mutations in the first α-helix of NpHAMP1 which adapted this sequence somewhat to the equivalent Tsr sequence was required to obtain a functional, i.e. signal-transducing HAMP tandem. Replacement of the entire α-helix NpAS11-mut5 by the equivalent sequence of HAMPTsr the chimeric HAMP monomer (AS1Tsr/NpAS2) was fully operational in that serine strongly inhibited AC activity. Furthermore, in combination with NpHAMP2 in tandem the sign of the output signal was inverted as predicted. This left us with two HAMP tandem constructs with opposite outputs of the serine signal as initiated by serine-binding to the periplasmic domain of Tsr. The differences between both constructs were confined to the first α-helix of the first HAMP domain in the tandem as all other segments remained unchanged. Both constructs received the same conformational signal from Tsr. One might then reasonably speculate that the first α-helix (α-helix-1) is ultimately responsible for formation of different ground states of the output domain which leads to differences in signal output. In a series of experiments...

‣ Untersuchungen zum Einfluss des Strahlenprotektors Bowman-Birk Protease Inhibitor auf die Signaltransduktionskaskade der SAPK; Investigation into the influence of the radioprotector Bowman-Birk protease inhibitor on the signal transduction of SAPK

Hermann, Jasmin Susann
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
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In einer Zelle werden durch UV -Strahlung eine Vielzahl von Signaltransduktionskaskaden induziert. In der vorliegenden Arbeit wurde untersucht, ob die strahlenprotektive Wirkung des Bowman-Birk Protease Inhibitors mit der Modulation solcher durch Strahlung induzierbarer Signaltransduktionskaskaden in Zusammenhang steht. Betrachtet wurde hierzu die Kaskade der 'stress activated protein kinase' (SAPK), einem Mitglied der MAPK Kaskade. Es wurden klonogene Assays und molekulare Untersuchungen auf Proteinebene mittels Western Blots an normalen humanen Hautfibroblasten durchgeführt. Die Untersuchungen zeigen, dass eine Inkubation der Hautfibroblasten mit BBI nicht zu einer Beeinflussung der SAPK-Kaskade führt. Auch eine Aktivierung der SAPK durch Anisomycin, einem spezifischen Aktivator der SAPK, vor einer UVB Bestrahlung, zur eventuelle Simulierung des BBI-Effekts, zeigt keinen strahlenprotektiven Effekt. Beide Ergebnisse geben Hinweise darauf, dass der molekulare Mechanismus, der der strahlenprotektiven Wirkung des BBI zugrunde liegt, nicht auf einer frühzeitigen Aktivierung der SAPK beruht. In den Untersuchungen zeigt sich jedoch die Beeinflussung einer anderen Kinase innerhalb der MAPK-Kaskade durch BBI. Diese Kinase entspricht mit großer Wahrscheinlichkeit der 'extracellular-signal regulated kinase' (ERK). Bereits nach kurzer Inkubation der Fibroblasten mit BBI kann eine Aktivierung dieser Kinase gesehen werden. Damit kann die These gestützt werden...

‣ Clonagem do Receptor de ACTH de células adrenocorticais Y-1 de camundongo e expressão em fibroblastos 3T3 e células de AR-1 para elucidação de vias de transdução de sinal; Cloning of ACTH receptor from mouse Y1 adrenocortical cells and expression in to mouse 3T3 fibroblasts and AR-1 cells for the study of signal transduction pathways.

Forti, Fábio Luís
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 01/02/2001 Português
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O hormônio adrenocorticotrópico, ACTH, regula função (esteroidogênese) e proliferação das células da córtex das glândulas adrenais através de um único receptor específico, ACTHR, que pertence à superfamília GPCR (G-protein coupled receptors). Embora o ACTHR tenha sido clonado há 8 anos, os mecanismos moleculares das ações mitogênica e anti-mitogênica de ACTH permanecem obscuros, cuja elucidação é objeto de estudo deste trabalho. A abordagem experimental consistiu na clonagem do ACTHR de células adrenocorticais Y-1 de camundongo e expressão funcional em fibroblastos 3T3 e células AR-1. Clones transfectantes, expressando estavelmente ACTHR, mostraram-se responsivos a ACTH através de: a) ativação de adenilato ciclase e b) indução de genes das famílias fos e jun. Por outro lado, medidas de síntese de DNA e proliferação celular indicam que ACTH não tem nenhum efeito mitogênico ou anti-mitogênico nos transfectantes ACTHR. O gene c-fos foi usado como alvo para testar vias de transdução de sinal ativadas por ACTH nos transfectantes 3T3 ACTHR. Estes testes mostraram que PKA, PKC e MAPK tem pouca ou nenhuma participação na indução de c-fos por ACTH nos clones 3T3 ACTHR, sugerindo que ACTHR pode ativar vias ainda não identificadas e motivando a busca de novas vias ativadas por ACTH nas células Y-1. Verificou-se que células Y-1 apresentam níveis constitutivamente elevados de AKT/PKB ativada (fosforilada)...