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Putative Targets (putative + target)
Terms modified by Putative Targets Selected AbstractsVessel density assessed by endoglin expression in breast carcinomas with different expression profilesHISTOPATHOLOGY, Issue 5 2009Nair Lopes Aims:, To evaluate the relationship between microvessel density assessed by endoglin expression and the molecular subtypes of human invasive breast carcinomas and whether there is evidence to indicate that angiogenesis could be a putative target for therapy in specific subsets of breast cancer. Methods and results:, We studied a series of 161 breast carcinomas, but information was available on only 142 tumours. We correlated endoglin expression with distinct breast carcinoma subgroups classified according to immunohistochemical profiling. Additionally, we compared it with other biomarkers for the aggressive basal-like subset and with available histopathological data. Although the basal-like subtype has higher microvessel density, there are no significant differences with the other molecular subtypes of breast cancer. Conclusions:, This study found no significant differences in tumour vascularity in different molecular subtypes of breast cancer. [source] A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands,THE JOURNAL OF PATHOLOGY, Issue 3 2009E Chanudet Abstract The genetic basis of MALT lymphoma is largely unknown. Characteristic chromosomal translocations are frequently associated with gastric and pulmonary cases, but are rare at other sites. We compared the genetic profiles of 33 ocular adnexal and 25 pulmonary MALT lymphomas by 1 Mb array,comparative genomic hybridization (CGH) and revealed recurrent 6q23 losses and 6p21.2,6p22.1 gains exclusive to ocular cases. High-resolution chromosome 6 tile-path array,CGH identified NF-,B inhibitor A20 as the target of 6q23.3 deletion and TNFA/B/C locus as a putative target of 6p21.2,22.1 gain. Interphase fluorescence in situ hybridization showed that A20 deletion occurred in MALT lymphoma of the ocular adnexa (8/42 = 19%), salivary gland (2/24 = 8%), thyroid (1/9 = 11%) and liver (1/2), but not in the lung (26), stomach (45) and skin (13). Homozygous deletion was observed in three cases. A20 deletion and TNFA/B/C gain were significantly associated (p < 0.001) and exclusively found in cases without characteristic translocation. In ocular cases, A20 deletion was associated with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis (p = 0.007), a higher proportion of relapse (67% versus 37%) and a shorter relapse-free survival (p = 0.033). A20 deletion and gain at TNFA/B/C locus may thus play an important role in the development of translocation-negative MALT lymphoma. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Ion-dependent gating of kainate receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 1 2010Derek Bowie Ligand-gated ion channels are an important class of signalling protein that depend on small chemical neurotransmitters such as acetylcholine, l -glutamate, glycine and ,-aminobutyrate for activation. Although numerous in number, neurotransmitter substances have always been thought to drive the receptor complex into the open state in much the same way and not rely substantially on other factors. However, recent work on kainate-type (KAR) ionotropic glutamate receptors (iGluRs) has identified an exception to this rule. Here, the activation process fails to occur unless external monovalent anions and cations are present. This absolute requirement of ions singles out KARs from all other ligand-gated ion channels, including closely related AMPA- and NMDA-type iGluR family members. The uniqueness of ion-dependent gating has earmarked this feature of KARs as a putative target for the development of selective ligands; a prospect all the more compelling with the recent elucidation of distinct anion and cation binding pockets. Despite these advances, much remains to be resolved. For example, it is still not clear how ion effects on KARs impacts glutamatergic transmission. I conclude by speculating that further analysis of ion-dependent gating may provide clues into how functionally diverse iGluRs families emerged by evolution. Consequently, ion-dependent gating of KARs looks set to continue to be a subject of topical inquiry well into the future. [source] Calmodulin activity and cAMP signalling modulate growth and apical secretion in pollen tubesTHE PLANT JOURNAL, Issue 6 2004Cláudia Rato Summary Our present understanding implicates both calmodulin (CaM) and 3,,5,-cyclicAMP (cAMP) in the regulation of pollen tube growth. However, downstream molecules of these signalling pathways and the cellular processes they modulate remain largely unknown. In order to elucidate the role of CaM, we mapped its activity in growing pollen tubes. 2-chloro-(,-amino-Lys75)-[6-4-(N,N, -diethylaminophenyl)-1,3,5-triazin-4-yl]-calmodulin (TA-CaM) and fluorescein-calmodulin (FL-CaM), fluorescent analogues of CaM, were loaded into pollen tubes and CaM activity was mapped by fluorescence ratio imaging. It was found that CaM activity exhibits a tip-focused gradient, similar to the distribution of cytosolic-free calcium ([Ca2+]c). In long pollen tubes, apical CaM activity was also found to oscillate with a period similar to [Ca2+]c (40,80 sec). This oscillatory behaviour was not observed in small pollen tubes or in tubes that had stopped growing. Changes in CaM activity within the dome of the pollen tube apex resulting from the photolysis of caged photolysis of RS-20 (a peptide antagonist of CaM) induced re-orientation of the growth axis, suggesting that CaM is also involved in the guidance mechanism. CaM activity was strongly modulated by intracellular changes in cAMP (induced by activators and antagonists of adenylyl cyclase). These results indicate that the action of this protein is dependent not solely on [Ca2+]c but also on a cross-talk with other signalling pathways. A putative target of this cross-talk is the secretory machinery as observed in pollen tubes loaded with the FM (N -(3-triethylammoniumpropyl)-4-(4-dibutylamino)styryl)pyridinium dibromide 1-43 dye and exposed to different antagonists and activators of these molecules. Our data thus suggest that pollen tube growth and orientation depend on an intricate cross-talk between multiple signalling pathways in which CaM is a key element. [source] ITCH is a putative target for a novel 20q11.22 amplification detected in anaplastic thyroid carcinoma cells by array-based comparative genomic hybridizationCANCER SCIENCE, Issue 10 2008Takaya Ishihara Anaplastic thyroid carcinoma (ATC) is one of the most virulent of all human malignancies, with a mean survival time among patients of less than 1 year after diagnosis. To date, however, cytogenetic information on this disease has been very limited. During the course of a program to screen a panel of ATC cell lines for genomic copy-number aberrations using array-based comparative genomic hybridization, we identified a high-level amplification of the ITCH gene, which is mapped to 20q11.22 and belongs to the homologous to the E6-associated protein carboxylterminus ubiquitin ligase family. The expression of ITCH was increased in 4 of 14 ATC cell lines (28.6%), including 8305C in which there was a copy-number amplification of this gene, and six of seven primary cases (85.7%). Among the primary thyroid tumors, a considerable number of ITCH high expressers was found in ATC (40/45, 88.9%), papillary thyroid carcinoma (25/25, 100%), and papillary microcarcinoma (25/25, 100%). Furthermore, knockdown of ITCH by specific small interfering RNA significantly inhibited the growth of ITCH-overexpressing cells, whereas ectopic overexpression of ITCH promoted growth of ATC cell lines with relatively weak expression. These observations indicate ITCH to be the most likely target for 20q11.22 amplification and to play a crucial role in the progression of thyroid carcinoma. (Cancer Sci 2008; 99: 1940,1949) [source] Docking Studies of Structurally Diverse Antimalarial Drugs Targeting PfATP6: No Correlation between in,silico Binding Affinity and in,vitro Antimalarial Activity.CHEMMEDCHEM, Issue 9 2009Fatima Bousejra-El Garah Abstract PfATP6, a calcium-dependent ATPase of Plasmodium falciparum, is considered the putative target of the antimalarial drug artemisinin and its derivatives. Herein, the 3D structure of PfATP6 was modeled on the basis of the crystal structure of SERCA,1a, the mammalian homologue. Model validation was achieved using protein structure checking tools. AutoDock4 was used to predict the binding affinities of artemisinin (and analogues) and various other antimalarial agents for PfATP6, for which in,vitro activity is also reported. No correlation was found between the affinity of the compounds for PfATP6 predicted by AutoDock4 and their antimalarial activity. [source] CXCL10-induced cell death in neurons: role of calcium dysregulationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006Yongjun Sui Abstract Chemokines play a key role in the regulation of central nervous system disease. CXCL10 over-expression has been observed in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease and HIV-associated dementia. More recent studies by others and us have shown that CXCL10 elicits apoptosis in fetal neurons. The mechanism of CXCL10-mediated neurotoxicity, however, remains unclear. In this study, we provide evidence for the direct role of Ca2+ dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca2+ and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca2+ elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca2+, which is available for uptake by the mitochondria, is associated with membrane permeabilization and cytochrome c release from this compartment. The released cytochrome c then activates the initiator active caspase-9. This initiator caspase sequentially activates the effector caspase-3, ultimately leading to apoptosis. This study identifies the temporal signaling cascade involved in CXCL10-mediated neuronal apoptosis and provides putative targets for pharmaceutical intervention of neurological disorders associated with CXCL10 up-regulation. [source] miR-20b modulates VEGF expression by targeting HIF-1, and STAT3 in MCF-7 breast cancer cells,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2010Sandra Cascio MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of different genes, including genes involved in cancer progression. A functional link between hypoxia, a key feature of the tumor microenvironment, and miRNA expression has been documented. We investigated whether and how miR-20b can regulate the expression of vascular endothelial growth factor (VEGF) in MCF-7 breast cancer cells under normoxic and hypoxia-mimicking conditions (CoCl2 exposure). Using immunoblotting, ELISA, and quantitative real-time PCR, we demonstrated that miR-20b decreased VEGF protein levels at 4 and 24,h following CoCl2 treatment, and VEGF mRNA at 4,h of treatment. In addition, miR-20b reduced VEGF protein expression in untreated cells. Next, we investigated the molecular mechanism by which pre-miR-20b can affect VEGF transcription, focusing on hypoxia inducible factor 1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), transcriptional inducers of VEGF and putative targets of miR-20b. Downregulation of VEGF mRNA by miR-20b under a 4,h of CoCl2 treatment was associated with reduced levels of nuclear HIF-1, subunit and STAT3. Chromatin immunoprecipitation (ChIP) assays revealed that HIF-1,, but not STAT3, was recruited to the VEGF promoter following the 4,h of CoCl2 treatment. This effect was inhibited by transfection of cells with pre-miR-20b. In addition, using siRNA knockdown, we demonstrated that the presence of STAT3 is necessary for CoCl2 -mediated HIF-1, nuclear accumulation and recruitment on VEGF promoter. In summary, this report demonstrates, for the first time, that the VEGF expression in breast cancer cells is mediated by HIF-1 and STAT3 in a miR-20b-dependent manner. J. Cell. Physiol. 224:242,249, 2010 © 2010 Wiley-Liss, Inc. [source] Promoting directional axon growth from neural progenitors grafted into the injured spinal cordJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2010Joseph F. Bonner Abstract Spinal cord injury (SCI) is a devastating condition characterized by disruption of axonal connections, failure of axonal regeneration, and loss of motor and sensory function. The therapeutic promise of neural stem cells has been focused on cell replacement, but many obstacles remain in obtaining neuronal integration following transplantation into the injured CNS. This study investigated the neurotransmitter identity and axonal growth potential of neural progenitors following grafting into adult rats with a dorsal column lesion. We found that using a combination of neuronal and glial restricted progenitors (NRP and GRP) produced graft-derived glutamatergic and GABAergic neurons within the injury site, with minimal axonal extension. Administration of brain-derived neurotrophic factor (BDNF) with the graft promoted modest axonal growth from grafted cells. In contrast, injecting a lentiviral vector expressing BDNF rostral into the injured area generated a neurotrophin gradient and promoted directional growth of axons for up to 9 mm. Animals injected with BDNF lentivirus (at 2.5 and 5.0 mm) showed significantly more axons and significantly longer axons than control animals injected with GFP lentivirus. However, only the 5.0-mm-BDNF group showed a preference for extension in the rostral direction. We concluded that NRP/GRP grafts can be used to produce excitatory and inhibitory neurons, and neurotrophin gradients can guide axonal growth from graft-derived neurons toward putative targets. Together they can serve as a building block for neuronal cell replacement of local circuits and formation of neuronal relays. © 2009 Wiley-Liss, Inc. [source] A membrane-bound FtsH protease is involved in osmoregulation in Synechocystis sp.MOLECULAR MICROBIOLOGY, Issue 1 2007PCC 6803: the compatible solute synthesizing enzyme GgpS is one of the targets for proteolysis Summary Protein quality control and proteolysis are involved in cell maintenance and environmental acclimatization in bacteria and eukaryotes. The AAA protease FtsH2 of the cyanobacterium Synechocystis sp. PCC 6803 was identified during a screening for mutants impaired in osmoregulation. The ftsH2, mutant was salt sensitive because of a decreased level of the osmoprotectant glucosylglycerol (GG). In spite of wild type-like transcription of the ggpS gene in ftsH2, cells the GgpS protein content increased but only low levels of GgpS activity were observed. Consequently, salt tolerance of the ftsH2, mutant decreased while addition of external osmolyte complemented the salt sensitivity. The proteolytic degradation of the GgpS protein by FtsH2 was demonstrated by an in vitro assay using inverted membrane vesicles. The GgpS is part of a GG synthesizing complex, because yeast two-hybrid screens identified a close interaction with the GG-phosphate phosphatase. Besides GgpS as the first soluble substrate of a cyanobacterial FtsH protease, several other putative targets were identified by a proteomic approach. We present a novel molecular explanation for the salt-sensitive phenotype of bacterial ftsH, mutants as the result of accumulation of inactive enzymes for compatible solute synthesis, in this case GgpS the key enzyme of GG synthesis. [source] Analysis of the HLA class I associated peptide repertoire in a hepatocellular carcinoma cell line reveals tumor-specific peptides as putative targets for immunotherapyPROTEOMICS - CLINICAL APPLICATIONS, Issue 3 2007Iñaki Alvarez Abstract HLA class I molecules present peptides on the cell surface to CD8+ T cells. The repertoire of peptides that associate to class I molecules represents the cellular proteome. Therefore, cells expressing different proteomes could generate different class I-associated peptide repertoires. A large number of peptides have been sequenced from HLA class I alleles, mostly from lymphoid cells. On the other hand, T cell immunotherapy is a goal in the fight against cancer, but the identification of T cell epitopes is a laborious task. Proteomic techniques allow the definition of putative T cell epitopes by the identification of HLA natural ligands in tumor cells. In this study, we have compared the HLA class I-associated peptide repertoire from the hepatocellular carcinoma (HCC) cell line SK-Hep-1 with that previously described from lymphoid cells. The analysis of the peptide pool confirmed that, as expected, the peptides from SK-Hep-1 derive from proteins localized in the same compartments as in lymphoid cells. Within this pool, we have identified 12 HLA class I peptides derived from HCC-related proteins. This confirms that tumor cell lines could be a good source of tumor associated antigens to be used, together with MS, to define putative epitopes for cytotoxic T cells from cancer patients. [source] Identification of regulatory pathways involved in the reacquisition of root growth after salt stress in Medicago truncatulaTHE PLANT JOURNAL, Issue 1 2007Francisco Merchan Summary Root growth and function are determined by the action of environmental stresses through specific genes that adapt root development to these restrictive conditions. We have defined in vitro conditions affecting the growth and recovery of Medicago truncatula roots after a salt stress. A dedicated macroarray containing 384 genes, based on a large-scale subtractive hybridization approach, was constructed and used to analyze gene expression during salt stress and recovery of root growth from this stress. Several potential regulatory genes were identified as being linked to this recovery process: a novel RNA-binding protein, a small G-protein homologous to ROP9, a receptor-like kinase, two TF IIIA-like and an AP2-like transcription factors (TF), MtZpt2-1, MtZpt2-2 and MtAp2, and a histidine kinase associated with cytokinin transduction pathways. The two ZPT2-type TFs were also rapidly induced by cold stress in roots. By analyzing transgenic M. truncatula plants showing reduced expression levels of both TFs and affected in their capacity to recover root growth after a salt stress, we identified potential target genes that were either activated or repressed in these plants. Overexpression of MtZpt2-1 in roots conferred salt tolerance and affected the expression of three putative targets in the predicted manner: a cold-regulated A (CORA) homolog, a flower-promoting factor (FPF1) homolog and an auxin-induced proline-rich protein (PRP) gene. Hence, regulatory networks depending on TFIIIA-like transcription factors are involved in the control of root adaptation to salt stress. [source] Identification of survival-related genes of the phosphatidylinositol 3,-kinase signaling pathway in glioblastoma multiformeCANCER, Issue 7 2008Yolanda Ruano BcSc Abstract BACKGROUND Knowledge of the molecular mechanisms involved in the biology of glioblastoma multiforme (GBM) is essential for the identification of candidate prognostic markers, new putative therapeutic targets, and early detection strategies predictive of survival. METHODS The authors performed expression-profiling analyses in a series of primary GBMs by using complementary DNA microarrays. Validation of putative targets was performed in large series of GBMs by immunohistochemistry on tissue microarrays, real-time quantitative reverse transcription-polymerase chain reaction analysis, and Western blot analysis. RESULTS The expression signature consisted of 159 up-regulated genes and 186 down-regulated genes. Most of these genes were involved in cell adhesion, signal transduction, cell cycle, apoptosis, and angiogenesis. Among the genes from the molecular signature, annexin 1 (ANXA1) and ubiquitin-specific protease 7 (USP7) were evaluated in wider series of GBMs. ANXA1 analysis carried out in different types of gliomas revealed exclusive overexpression in astrocytomas. Furthermore, survival analysis by using functional clusters of genes related with cancer and glioma biology revealed 7 genes involved in the PI3K-signaling pathway that presented a significant association with clinical outcome. Among these genes, positive expression of BCL2-associated X protein (BAX) was associated significantly with better survival in a larger series of tumors. In addition, activation of the PI3K/Akt pathway was demonstrated in this set of GBMs. CONCLUSIONS The authors concluded that there is a significant role for PI3K pathway survival-related genes in patients with GBM, and putative prognostic markers associated with glioma tumorigenesis were identified. The detailed study of these candidate genes and the molecular pathways regulating PI3K activation reveal that they are promising targets for the clinical management of patients with glioma. Cancer 2008. © 2008 American Cancer Society. [source] | |||||||||||||