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Multiple Signaling Pathways (multiple + signaling_pathway)
Selected AbstractsExpression of the NET family member Zfp503 is regulated by hedgehog and BMP signaling in the limbDEVELOPMENTAL DYNAMICS, Issue 4 2008Edwina McGlinn Abstract The NET/Nlz family of zinc finger transcription factors contribute to aspects of developmental growth and patterning across evolutionarily diverse species. To date, however, these molecules remain largely uncharacterized in mouse and chick. We previously reported that limb bud expression of Zfp503, the mouse orthologue of zebrafish nlz2/znf503, is dependent on Gli3. Here, we show that Zfp503/Znf503 is expressed in a restricted pattern during mouse and chick embryogenesis, with particularly dynamic expression in the developing limbs, face, somites, and brain. We also add to our previous data on Gli3 regulation by showing that the anterior domain of Zfp503 expression in the mouse limb is responsive to genetic and nongenetic manipulation of hedgehog signaling. Finally, we demonstrate that posterior expression of Znf503 in the chick limb is responsive to bone morphogenetic protein (BMP) signaling, indicating that Zfp503/Znf503 may act at the nexus of multiple signaling pathways in development. Developmental Dynamics 237:1172,1182, 2008. © 2008 Wiley-Liss, Inc. [source] Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathwaysGLIA, Issue 10 2007Terra J. Frederick Abstract D-type cyclins are direct targets of extracellular signals and critical regulators of G1 progression. Our previous data demonstrated that IGF-I and FGF-2 synergize to enhance cyclin D1 expression, cyclin E/cdk2 complex activation, and S-phase entry in OP cells. Here, we provide a mechanistic explanation for how two growth factor signaling pathways converge on a major cell cycle regulator. IGF-I and FGF-2 differentially activate signaling pathways to coordinately promote cyclin D1 expression. We show that the p44/p42 MAPK signaling pathway is essential for FGF-2 induction of cyclin D1 mRNA. In contrast, blocking the PI3-Kinase pathway results in loss of IGF-I/FGF-2 synergistic induction of cyclin D1 protein levels. Moreover, the presence of IGF-I significantly enhances nuclear localization of cyclin D1, which also requires PI3K signaling. GSK-3,, a downstream target of the PI3K/Akt pathway, is phosphorylated in the presence of IGF-I in OPs. Consistent with a known role for GSK-3, in cyclin D1 degradation, we show that proteasome inhibition in OPs exposed to FGF-2 increased cyclin D1 levels, equivalent to levels seen in IGF-I/FGF-2 treated cells. Thus, we provide a model for cyclin D1 coordinate regulation where FGF-2 stimulation of the MAPK pathway promotes cyclin D1 mRNA expression while IGF-I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1. © 2007 Wiley-Liss, Inc. [source] Mechanisms of resistance to EGFR inhibitors in head and neck cancer,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 8 2009Jonathan B. Cooper BS Abstract Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that activates multiple signaling pathways, including phosphatidylinositol-3-kinase/v-AKT murine thymoma viral oncogene homolog protein (Akt), has long been a target of novel therapies. Despite universal EGFR expression in head and neck squamous cell carcinoma (HNSCC), the majority of patients do not respond to EGFR inhibitors. This review focuses on mechanisms of resistance to these agents in HNSCC, and how these may be unique when compared with other malignancies such as non-small cell lung and colorectal cancers. Published studies and abstracts reveal that there are likely several mechanisms underlying resistance, suggesting that different strategies will be required to improve efficacy of EGFR inhibitors in HNSCC. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [source] Functional analysis of CBP/p300 in embryonic orofacial mesenchymal cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2006D.R. Warner Abstract CREB binding protein (CBP) and the close structural homolog, p300, are nuclear coactivators of multiple signaling pathways that play important roles in embryonic development and cellular homeostasis. TGF, regulates the proliferation rate of many cell types and has been demonstrated to inhibit the growth rate of mouse embryonic maxillary mesenchymal (MEMM) cells. The role of CBP and p300 in TGF,-mediated control of proliferation of MEMM cells was thus investigated using an in vitro gene knockdown approach. TGF, reporter assays demonstrated that p300 mRNA knockdown via targeted siRNAs led to a reduction in the response to TGF,, whereas knockdown of CBP by the same approach had an insignificant effect. In MEMM cell proliferation assays, siRNA-mediated knockdown of CBP and/or p300 had little impact upon TGF,-mediated growth inhibition; however, the basal rate of proliferation was increased. Inhibition of p300 activity via overexpression of a dominant-negative mutant (p300,C/H3) led to significant inhibition of TGF,-mediated activation of p3TP-lux. As with the siRNA knockdown approach, p300,C/H3 also increased the basal rate of cell proliferation of MEMM cells. CBP/p300 siRNA knockdown had a significant but incomplete inhibition of TGF,-induction of matrix metalloproteinase-9 (gelatinase B) expression. These data demonstrate that p300 is involved in Smad-mediated transcription of p3TP-lux, however, its role (and that of CBP) in biological processes such as the control of cell proliferation and extracellular matrix metabolism is more complex and may be mediated via mechanisms beyond coactivator recruitment. J. Cell. Biochem. 99: 1374,1379, 2006. © 2006 Wiley-Liss, Inc. [source] Stimulation of macrophage TNF, production by orthopaedic wear particles requires activation of the ERK1/2/Egr-1 and NF-,B pathways but is independent of p38 and JNKJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2008Michelle A. Beidelschies Bone loss that causes aseptic loosening of orthopedic implants is initiated by pro-inflammatory cytokines produced by macrophages in response to implant-derived wear particles. MAPK and NF-,B signaling pathways are activated by the particles; however, it is not clear which of the signaling pathways are important for the initial response to the wear particles and which are only involved at later steps in the process, such as osteoclast differentiation. Here, we show that the ERK1/2, p38, JNK, and NF-,B pathways are rapidly activated by the wear particles but that only the ERK1/2 and NF-,B pathways are required for the initial response to the wear particles, which include increases in TNF, promoter activity, TNF, mRNA expression, and secretion of TNF, protein. Moreover, ERK1/2 activation by wear particles is also required for increased expression of the transcription factor Egr-1 as well as Egr-1's ability to bind to and activate the TNF, promoter. These results, together with our previous studies of the PI3K/Akt pathway, demonstrate that wear particles coordinately activate multiple signaling pathways and multiple transcription factors to stimulate production of pro-inflammatory cytokines, such as TNF,. The current study also demonstrates that the signaling pathways are activated to a much greater extent by wear particles with adherent endotoxin than by "endotoxin-free" wear particles. These results, together with those demonstrating the requirement for ERK1/2/Egr-1 and NF-,B, show that activation of these signaling pathways is responsible for the ability of adherent endotoxin to potentiate cytokine production, osteoclast differentiation, and bone loss induced by wear particles. J. Cell. Physiol. 217: 652,666, 2008. © 2008 Wiley-Liss, Inc. [source] AKT and MAPK signaling in KGF-treated and UVB-exposed human epidermal cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2007Lavinia Vittoria Lotti Regulation of proliferation and differentiation in keratinocyte is a complex and dynamic process that involves activation of multiple signaling pathways triggered by different growth factors. Keratinocyte growth factor (KGF) is not only a potent mitogen, but differently from other growth factors, is a potent inducer of differentiation. The MAP kinase and AKT pathways are involved in proliferation and differentiation of many cell types including keratinocytes. We investigated here the role of KGF in modulating AKT and MAPK activity during differentiation of human keratinocytes. Our results show that the mechanisms of action of KGF are dose-dependent and that a sustained activation of the MAPK signaling cascade causes a negative regulation of AKT. We also demostrated increasing expression of KGFR substrates, such as PAK4 during keratinocyte differentiation parallel to the receptor upregulation. J. Cell. Physiol. 212:633,642, 2007. © 2007 Wiley-Liss, Inc. [source] The Actin Cytoskeleton and Signaling Network during Pollen Tube Tip GrowthJOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 2 2010Ying Fu The organization and dynamics of the actin cytoskeleton play key roles in many aspects of plant cell development. The actin cytoskeleton responds to internal developmental cues and environmental signals and is involved in cell division, subcellular organelle movement, cell polarity and polar cell growth. The tip-growing pollen tubes provide an ideal model system to investigate fundamental mechanisms of underlying polarized cell growth. In this system, most signaling cascades required for tip growth, such as Ca2+ -, small GTPases- and lipid-mediated signaling have been found to be involved in transmitting signals to a large group of actin-binding proteins. These actin-binding proteins subsequently regulate the structure of the actin network, as well as the rapid turnover of actin filaments (F-actin), thereby eventually controlling tip growth. The actin cytoskeleton acts as an integrator in which multiple signaling pathways converge, providing a general growth and regulatory mechanism that applies not only for tip growth but also for polarized diffuse growth in plants. [source] Axon or dendrite? cell biology and molecular pathways for neuronal cell asymmetryJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2008Masashi Kishi Abstract Young neurons polarize by specializing axons and dendrites from immature neurites. After synapse formations, they transmit electrical activity along the axon-dendrite axis, thereby working as functional units of the neural circuits. This axon-dendrite asymmetry is referred to as neuronal polarity. Although a great number of cell biological studies in vitro had been performed, little was known about the molecular events that establish the polarity. In the last several years, rapid advancement in molecular and genetic studies has unraveled the multiple signaling pathways. This paper summarizes current perspectives on the cell and molecular biological mechanisms of the neuronal polarization, to clarify future directions in this growing research field. © 2007 Wiley-Liss, Inc. [source] REVIEW ARTICLE: Control of Interferon-Tau Expression During Early Pregnancy in RuminantsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2009Alan D. Ealy Problem, A type I interferon (IFN), termed IFN-tau (,), is responsible for the establishment and maintenance of early pregnancy in cattle and sheep. The control of IFN, gene (IFNT) expression is not completely understood. Method of study, This article will provide an overview of recent progress made in understanding the dynamic expression pattern of IFNT during pre- and peri-attachment conceptus development. Results, Several ubiquitous transcriptional regulators (Ets2 and AP1) and at least two trophectoderm factors (Cdx2 and Dlx3) control IFNT transcription during early pregnancy. Co-activators (CBP/p300) are also involved in this process. At least two uterine-derived factors (GM-CSF and FGF2) stimulate IFN-, production in bovine trophectoderm, and multiple signaling pathways are functionally linked with IFNT expression. Conclusion, Although understanding the regulation of IFNT expression is far from complete, considerable progress has been made in uncovering how uterine-derived factors and key placental-specific transcriptional regulators control IFNT expression. [source] Prognostic role of insulin-like growth factor receptor-1 expression in small cell lung cancerAPMIS, Issue 12 2009MYUNG HEE CHANG Insulin-like growth factor receptor-1 (IGFR-1) is a cellular membrane receptor which is overexpressed in many tumors and seems to play a critical role in anti-apoptosis. The insulin-like growth factor binding protein-3 (IGFBP-3) is known as a growth suppressor in multiple signaling pathways. The aim of this study was to determine IGFR-1 and IGFBP-3 expression in small-cell lung cancer (SCLC) and analyze the prognostic value in patients with SCLC. We analyzed IGFR-1 and IGFBP-3 expression in 194 SCLC tissues by immunohistochemical staining. Correlative analyses between IGFR-1 and IGFBP-3 expression in SCLC and clinicopathologic factors were performed. A total of 117 patients had extensive disease (ED) (60.3%) and 77 had limited disease (39.7%). With the median follow-up duration of 49.5 months (24,82 months), the median progression-free survival (PFS) and overall survival (OS) were 7.2 months [95% confidence interval (CI): 6.4,8.0 months] and 14.4 months (95% CI: 12.7,16 months), respectively. IGFR-1 expression was observed in 154 of the 190 tumor tissues, whereas there was no IGFBP-3 expression. Multivariate analysis showed that stage (p < 0.001), response rate (p < 0.001), and lactate dehydrogenase (LDH) levels (p < 0.001) were the independent prognostic factors for PFS, and age (p = 0.014), LDH level (p < 0.001), and stage (p < 0.001) for OS. The IGFR-1 positivity was not associated with PFS or OS in the entire cohort. Subgroup analysis revealed that OS was significantly longer in patients with IGFR-1-positive tissue than IGFR-1-negative tissue in SCLC-ED (p = 0.034). These results suggest that IGFR-1 expression may be useful as a prognostic marker in patients with SCLC-ED. [source] Protein phosphorylation and kinome profiling reveal altered regulation of multiple signaling pathways in B lymphocytes from patients with systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 8 2010Taher E. Taher Objective The cause of B lymphocyte hyperactivity and autoantibody production in systemic lupus erythematosus (SLE) remains unclear. Previously, we identified abnormalities in the level and translocation of signaling molecules in B cells in SLE patients. The present study was undertaken to examine the extent of signaling abnormalities that relate to altered B cell responses in SLE. Methods B lymphocytes from 88 SLE patients and 72 healthy controls were isolated from blood by negative selection. Protein tyrosine phosphorylation and cellular kinase levels were analyzed by Western blotting, flow cytometry, and a kinome array protocol. Changes in protein phosphorylation were determined in ex vivo B cells and following B cell receptor engagement. Results Differences in tyrosine phosphorylation in B cells from patients with SLE, compared with matched controls, were demonstrated. Further, the kinome array analysis identified changes in the activation of key kinases, i.e., the activity of phosphatidylinositol 3-kinase, which regulates survival and differentiation, was up-regulated and the activity of Rac and Rho kinases, which regulate the cytoskeleton and migration, was increased. In contrast, the activity of ATR, which regulates the cell cycle, was down-regulated in SLE patients compared with controls. Differences in signaling pathways were seen in all SLE B lymphocyte subsets that manifested phenotypic features of immature, mature, and memory cells. Conclusion This study revealed dysregulation in multiple signaling pathways that control key responses in B cells of SLE patients. Data generated in this study provide a molecular basis for further analysis of the altered B lymphocyte responses in SLE. [source] The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1CANCER SCIENCE, Issue 5 2009Junko H. Ohyashiki To evaluate the effect of deferasirox in human myeloid leukemia cells, and to identify the moleclular pathways responsible for antiproliferative effects on leukemia cells during chelation therapy, we performed gene expression profiling to focus on the pathway involved in the anticancer effect of deferasirox. The inhibitory concentration (IC50) of deferasirox was 17,50 µM in three human myeloid cell lines (K562, U937, and HL60), while those in fresh leukemia cells obtained from four patients it varied from 88 to 172 µM. Gene expression profiling using Affymerix GeneChips (U133 Plus 2.0) revealed up-regulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) encoding p21CIP, genes regulating interferon (i.e. IFIT1). Pathways related to iron metabolism and hypoxia such as growth differentiation factor 15 (GDF-15) and Regulated in development and DNA damage response (REDD1) were also prominent. Based on the results obtained from gene expression profiling, we particularly focused on the REDD1/mTOR (mammalian target of rapamycin) pathway in deferasirox-treated K562 cells, and found an enhanced expression of REDD1 and its down-stream protein, tuberin (TSC2). Notably, S6 ribosomal protein as well as phosphorylated S6, which is known to be a target of mTOR, was significantly repressed in deferasirox-treated K562 cells, and REDD1 small interfering RNA restored phosphorylation of S6. Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox. Deferasirox might not only have benefit for iron chelation but also may be an antiproliferative agent in some myeloid leukemias, especially patients who need both iron chelation and reduction of leukemia cells. (Cancer Sci 2009; 100: 970,977) [source] PP2C family members play key roles in regulation of cell survival and apoptosisCANCER SCIENCE, Issue 7 2006Shinri Tamura Although unlimited proliferation of cancer cells is supported by multiple signaling pathways involved in the regulation of proliferation, survival, and apoptosis, the molecular mechanisms coordinating these different pathways to promote the proliferation and survival of cancer cells have remained unclear. SAPK and integrin-ILK signaling pathways play key roles in the promotion of apoptosis and cell proliferation/survival, respectively. Studies of TNF,- and H2O2 -induced apoptosis revealed that ASK1, a component of the SAPK system, mediates the TNF, and H2O2 signaling of apoptosis. ASK1 is activated by autophosphorylation of a specific threonine residue (T845) following TNF, stimulation. Our recent studies indicate that PP2C,, a member of the PP2C family, associates with and inactivates ASK1 by dephosphorylating T845. In contrast, PP2C,/ILKAP, a second PP2C family member, activates ASK1 by enhancing cellular phosphorylation of T845. PP2C,/ILKAP also forms a complex with ILK1 to inhibit the GSK3,-mediated integrin-ILK1 signaling in vivo, inhibiting cell cycle progression. These observations raise the possibility that PP2C,/ILKAP acts to control the cross-talk between integrin-induced and TNF,-induced signaling pathways, inhibiting the former and stimulating the latter, thereby inhibiting proliferation and survival and promoting the apoptosis of cancer cells. (Cancer Sci 2006; 97: 563,567) [source] | |||||||||||||