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Antenatal steroid and tracheal occlusion restore vascular endothelial growth factor receptors in congenital diaphragmatic hernia rat model

SCHMIDT, Augusto F.; GONCALVES, Frances L. L.; NASSR, Azize C. C.; PEREIRA, Luis A. V. D.; FARMER, Diana; SBRAGIA, Lourenco
Fonte: MOSBY-ELSEVIER Publicador: MOSBY-ELSEVIER
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
85.92%
OBJECTIVE: Investigate the effects of antenatal steroids and tracheal occlusion on pulmonary expression of vascular endothelial growth factor receptors in rats with nitrofen-induced congenital diaphragmatic hernia. STUDY DESIGN: Fetuses were exposed to nitrofen at embryonic day 9.5. Subgroups received dexamethasone or were operated on for tracheal occlusion, or received combined treatment. Morphologic variables were recorded. To analyze vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2 expression, we performed Western blotting and immunohistochemistry. Morphologic variables were analyzed by analysis of variance and immunohistochemistry by Kruskal-Wallis test. RESULTS: Congenital diaphragmatic hernia decreased body weight, total lung weight, and lung-to-body weight ratio. Tracheal occlusion increased total lung weight and lung-to-body weight ratio (P < .05). Fetuses with congenital diaphragmatic hernia had reduced vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2 expression, whereas steroids and tracheal occlusion increased their expression. Combined treatment increased expression of receptors, but had no additive effect. CONCLUSION: Vascular endothelial growth factor signaling disruption may be associated with pulmonary hypertension in congenital diaphragmatic hernia. Tracheal occlusion and steroids provide a pathway for restoring expression of vascular endothelial growth factor receptors.

Expression of fibroblast growth factor-8 and its cognate receptors, fibroblast growth factor receptor (FGFR)-3c and-4, in fetal bovine preantral follicles

Buratini, J.; Glapinski, V. F.; Giometti, I. C.; Teixeira, A. B.; Costa, I. B.; Avellar, MCW; Barros, C. M.; Price, C. A.
Fonte: Wiley-Blackwell Publicador: Wiley-Blackwell
Tipo: Artigo de Revista Científica Formato: 255-261
ENG
Relevância na Pesquisa
85.85%
Paracrine cell signaling is thought to be important for ovarian follicle development, and a role for some members of the fibroblast growth factor (FGF) family have been suggested. In the present study, we tested the hypothesis that FGF-8 and its cognate receptors (FGFR-3c and FGFR-4) are expressed in bovine preantral follicles. Reverse transcription-polymerase chain reaction was used to amplify bovine FGF-8, FGFR-3c, and FGFR-4 from preantral follicle samples and a variety of fetal and adult tissues. All three genes were widely expressed in fetal tissues, with a restricted expression pattern in adult tissues. FGF-8 and FGFR-3c were expressed in secondary follicles in 70% of fetuses examined, whereas FGFR-4 expression was significantly less frequent (20%). FGFR-3c expression frequency was significantly lower in primordial compared to secondary follicles, and FGF-8 expression showed a similar trend. FGFR-4 was only observed when all follicle classes of an individual were expressing both FGF-8 and FGFR-3c. We conclude that FGF-8 and its receptors are expressed in preantral follicles in a developmentally regulated manner. (C) 2005 Wiley-Liss, Inc.

Antenatal steroid and tracheal occlusion restore vascular endothelial growth factor receptors in congenital diaphragmatic hernia rat model

SCHMIDT, Augusto F.; GONCALVES, Frances L. L.; NASSR, Azize C. C.; PEREIRA, Luis A. V. D.; FARMER, Diana; SBRAGIA, Lourenco
Fonte: MOSBY-ELSEVIER Publicador: MOSBY-ELSEVIER
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
85.92%
OBJECTIVE: Investigate the effects of antenatal steroids and tracheal occlusion on pulmonary expression of vascular endothelial growth factor receptors in rats with nitrofen-induced congenital diaphragmatic hernia. STUDY DESIGN: Fetuses were exposed to nitrofen at embryonic day 9.5. Subgroups received dexamethasone or were operated on for tracheal occlusion, or received combined treatment. Morphologic variables were recorded. To analyze vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2 expression, we performed Western blotting and immunohistochemistry. Morphologic variables were analyzed by analysis of variance and immunohistochemistry by Kruskal-Wallis test. RESULTS: Congenital diaphragmatic hernia decreased body weight, total lung weight, and lung-to-body weight ratio. Tracheal occlusion increased total lung weight and lung-to-body weight ratio (P < .05). Fetuses with congenital diaphragmatic hernia had reduced vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2 expression, whereas steroids and tracheal occlusion increased their expression. Combined treatment increased expression of receptors, but had no additive effect. CONCLUSION: Vascular endothelial growth factor signaling disruption may be associated with pulmonary hypertension in congenital diaphragmatic hernia. Tracheal occlusion and steroids provide a pathway for restoring expression of vascular endothelial growth factor receptors.

Epidermal growth factor receptor inhibitors in non-small cell lung cancer: current status and future perspectives

Zükin,Mauro
Fonte: Associação Médica Brasileira Publicador: Associação Médica Brasileira
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2012 EN
Relevância na Pesquisa
85.77%
Two classes of epidermal growth factor receptor (EGFR) inhibitors are currently available for clinical use: tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies. The introduction of pharmacological agents that are able to inhibit EGFR represents an important step in the management of patients with advanced non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide. The use of EGFR inhibitors has not only led to meaningful therapeutic gains for patients, but has also expanded our knowledge about the disease itself, as it is now recognized that activating mutations of EGFR play a pathogenetic role in NSCLC, especially in adenocarcinoma, patients who never smoked or former light smokers, females, and Asian individuals. Patients with NSCLC and one or more of these features are more likely to harbor tumors with EGFR mutations, and hence to respond to TKIs, than individuals without these features. Currently, TKIs are considered by many as the treatment of first choice in both the first- and second-line treatment of patients with clinical or molecular predictors of therapeutic benefit, and chemotherapy is a second option in these cases, especially when activating mutations of EGFR are present. Moreover, TKIs and anti-EGFR antibodies may be used in other settings...

Immunohistochemical expression of the epidermal growth factor receptor (EGFR) in colorectal carcinoma: relation with clinicopathological parameters

Azevedo,Maurício Andrade; Souza,Bianca Doimo; Mader,Ana Maria Amaral Antonio; Martins,Lourdes Conceição; Waisberg,Jaques
Fonte: Sociedade Brasileira de Coloproctologia Publicador: Sociedade Brasileira de Coloproctologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2011 EN
Relevância na Pesquisa
85.77%
Introduction: The study of tissue immunostaining of the epidermal growth factor receptor (EGFR) may contribute with the understanding of its role in the prognosis of colorectal carcinoma. Objective: To analyze the immunohistochemical expression of EGFR in colorectal carcinoma tissues and transitional tumor-mucosa and mucosa adjacent to neoplasia, and its relation with cancer. Method: The study was conducted with 40 patients with colorectal carcinoma who had surgery with curative intent in order to analyze the immunoexpression of EGFR with anti-EGFR. We used parametric and nonparametric tests. Results: The immunohistochemical expression of EGFR in tumor samples showed a significant difference as to the level of immunostaining in tissue specimens of transitional tumor-mucosa (p=0.01) and the level of immunoreactivity in tissues of the adjacent mucosa (p=0, 04). The immunoexpression of EGFR showed no significant relation with the size of the tumor, angiolymphatic invasion, neural invasion, cellular differentiation, level of carcinoma infiltration in the intestinal wall, lymph node metastases and liver metastases. Conclusions: The EGFR showed a more intense expression in the mucosa of colorectal carcinoma than in the transitional epithelium and adjacent non-neoplastic mucosa. The immunoexpression of EGFR did not correlate with pathological parameters of colorectal carcinoma and liver metastases.

Receptor Heterodimerization: Essential Mechanism for Platelet-Derived Growth Factor-Induced Epidermal Growth Factor Receptor Transactivation

Saito, Yuji; Haendeler, Judith; Hojo, Yukihiro; Yamamoto, Kei; Berk, Bradford C.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /10/2001 EN
Relevância na Pesquisa
75.87%
Previous studies showed that the epidermal growth factor receptor (EGFR) can be transactivated by platelet-derived growth factor (PDGF) stimulation and that EGFR transactivation is required for PDGF-stimulated cell migration. To investigate the mechanism for cross talk between the PDGF β receptor (PDGFβR) and the EGFR, we stimulated rat aortic vascular smooth muscle cells (VSMC) with 20 ng of PDGF/ml. Transactivation of the EGFR, defined by receptor tyrosine phosphorylation, occurred with the same time course as PDGFβR activation. Basal formation of PDGFβR-EGFR heterodimers was shown by coimmunoprecipitation studies, and interestingly, disruption of this receptor heterodimer abolished EGFR transactivation. Breakdown of the heterodimer was observed when VSMC were pretreated with antioxidants or with a Src family kinase inhibitor. Disruption of heterodimers decreased ERK1 and ERK2 activation by PDGF. Although PDGF-induced PDGFβR activation was abolished after pretreatment with 1 μM AG1295 (a specific PDGF receptor kinase inhibitor), EGFR transactivation was still observed, indicating that PDGFβR kinase activity is not required. In conclusion, our data demonstrate that the PDGFβR and the EGFR form PDGFβR-EGFR heterodimers basally...

Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants

Park, Angela K.J.; Francis, Joshua M.; Park, Woong-Yang; Park, Joon-Oh; Cho, Jeonghee
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
95.79%
Genomic alterations targeting the Epidermal Growth Factor Receptor (EGFR) gene have been strongly associated with cancer pathogenesis. The clinical effectiveness of EGFR targeted therapies, including small molecules directed against the kinase domain such as gefitinib, erlotinib and afatinib, have been proven successful in treating non-small cell lung cancer patients with tumors harboring EGFR kinase domain mutations. Recent large-scale genomic studies in glioblastoma and lung cancer have identified an additional class of oncogenic mutations caused by the intragenic deletion of carboxy-terminal coding regions. Here, we report that combinations of exonic deletions of exon 25 to 28 lead to the oncogenic activation of EGF receptor in the absence of ligand and consequent cellular transformation, indicating a significant role of C-terminal domain in modulating EGFR activation. Furthermore, we show that the oncogenic activity of the resulting C-terminal deletion mutants are efficiently inhibited by EGFR-targeted drugs including erlotinib, afatinib, dacomitinib as well as cetuximab, expanding the therapeutic rationale of cancer genome-based EGFR targeted approaches. Finally, in vivo and in vitro preclinical studies demonstrate that constitutive asymmetric dimerization in mutant EGFR is a key mechanism for oncogenic activation and tumorigenesis by C-terminal deletion mutants. Therefore...

A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome

Muenke, M.; Gripp, K.; McDonald-McGinn, D.; Gaudenz, K.; Whitaker, L.; Bartlett, S.; Markowitz, R.; Robin, N.; Nwokoro, N.; Mulvihill, J.; Losken, H.; Mulliken, J.; Guttmacher, A.; Wilroy, R.; Clarke, L.; Hollway, G.; Ades, L.; Haan, E.; Mulley, J.; Cohen
Fonte: UNIV CHICAGO PRESS Publicador: UNIV CHICAGO PRESS
Tipo: Artigo de Revista Científica
Publicado em //1997 EN
Relevância na Pesquisa
85.81%
The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.; M. Muenke...

A potential autocrine role for vascular endothelial growth factor in prostate cancer

Jackson, M.; Roberts, J.; Heckford, S.; Ricciardelli, C.; Stahl, J.; Horsfall, D.; Tilley, W.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2002 EN
Relevância na Pesquisa
75.9%
Vascular endothelial growth factor (VEGF) is a peptide growth factor specific for the tyrosine kinase receptors VEGF receptor-1 and -2 (VEGFR-1 and R-2). Whereas VEGF has well-defined actions on the vasculature, including the stimulation of endothelial cell growth and motility and blood vessel permeability, the function of the VEGF/ receptor pathway in other cell types is largely unknown. Recently, VEGFR-1 and R-2 expression has been reported in prostate tumor cells. In this study, we demonstrate that these receptors colocalize with VEGF in prostate tumor cells, prostatic intraepithelial neoplasia, and the basal cells of normal glands. Furthermore, in comparison with normal glands, the expression of VEGFR-1 and R-2 is increased in prostatic intraepithelial neoplasia and malignant cells in well and moderately differentiated prostate cancer but is decreased in poorly differentiated cancer. Culture of the prostate cancer cell line LNCaP in the presence of recombinant human VEGF165 resulted in a 50% increase in [3H]thymidine uptake by these cells and recruitment of quiescent cells into the cell cycle. This effect of recombinant human VEGF165 was abolished by neutralizing antisera to VEGFR-2. These data suggest that VEGF may not only mediate neovascularization associated with prostate cancer progression but may also directly stimulate prostate tumor cells via VEGFR-2-dependent autocrine and/or paracrine mechanisms.; Michael W. Jackson...

The structure and function of vertebrate fibroblast growth factor receptor 1

Groth, C.; Lardelli, M.
Fonte: Univ Basque Country Press Publicador: Univ Basque Country Press
Tipo: Artigo de Revista Científica
Publicado em //2002 EN
Relevância na Pesquisa
95.82%
The vertebrate fibroblast growth factor receptor 1 (FGFR1) is alternatively spliced generating multiple splice variants that are differentially expressed during embryo development and in the adult body. The restricted expression patterns of FGFR1 isoforms, together with differential expression and binding of specific ligands, leads to activation of common FGFR1 signal transduction pathways, but may result in distinctively different biological responses as a result of differences in cellular context. FGFR1 isoforms are also present in the nucleus in complex with various fibroblast growth factors where they function to regulate transcription of target genes.; Casper Groth and Michael Lardelli

Roles of epidermal growth factor family in the regulation of postnatal somatic growth

Xian, C.
Fonte: Endocrine Soc Publicador: Endocrine Soc
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
Relevância na Pesquisa
75.84%
Ligands of the epidermal growth factor receptor (EGF-R), known to be important for supporting tissue development particularly in the gut and brain, have also been implicated in regulating postnatal somatic growth. Although optimal levels of both milk-borne and endogenous EGF-R ligands are important for supporting postnatal somatic growth through regulating gastrointestinal growth and maturation, supraphysiological levels of EGF-R ligands can cause retarded and disproportionate growth and alter body composition because they can increase growth of epithelial tissues but decrease masses of muscle, fat, and bone. Apart from their indirect roles in influencing growth, possibly via regulating levels of IGF-I and IGF binding proteins, EGF-R ligands can regulate bone growth and modeling directly because they can enhance proliferation but suppress maturation of growth plate chondrocytes (for building a calcified cartilage scaffold for bone deposition), stimulate proliferation but inhibit differentiation of osteoblasts (for depositing bone matrix), and promote formation and function of osteoclasts (for resorption of calcified cartilage or bone). In addition, EGF-like ligands, particularly amphiregulin, can be strongly regulated by PTH, an important regulatory factor in bone modeling and remodeling. Finally...

Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II

Alvino, C.; Ong, S.; McNeil, K.; Delaine, C.; Booker, G.; Wallace, J.; Forbes, B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
75.91%
Background: Insulin-like growth factor-II (IGF-II) promotes cell proliferation and survival and plays an important role in normal fetal development and placental function. IGF-II binds both the insulin-like growth factor receptor (IGF-1R) and insulin receptor isoform A (IR-A) with high affinity. Interestingly both IGF-II and the IR-A are often upregulated in cancer and IGF-II acts via both receptors to promote cancer proliferation. There is relatively little known about the mechanism of ligand induced activation of the insulin (IR) and IGF-1R. The recently solved IR structure reveals a folded over dimer with two potential ligand binding pockets arising from residues on each receptor half. Site-directed mutagenesis has mapped receptor residues important for ligand binding to two separate sites within the ligand binding pocket and we have recently shown that the IGFs have two separate binding surfaces which interact with the receptor sites 1 and 2. Methodology/Principal Findings: In this study we describe a series of partial IGF-1R and IR agonists generated by mutating Glu12 of IGF-II. By comparing receptor binding affinities, abilities to induce negative cooperativity and potencies in receptor activation, we provide evidence that residue Glu12 bridges the two receptor halves leading to receptor activation. Conclusions/Significance: This study provides novel insight into the mechanism of receptor binding and activation by IGFII...

Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: Preclinical evaluation and results of the Phase II DUX Study in chemotherapy-refractory, advanced colorectal cancer

Weickhardt, A.; Price, T.; Chong, G.; Gebski, V.; Pavlakis, N.; Johns, T.; Azad, A.; Skrinos, E.; Fluck, K.; Dobrovic, A.; Salemi, R.; Scott, A.; Mariadason, J.; Tebbutt, N.
Fonte: Amer Soc Clinical Oncology Publicador: Amer Soc Clinical Oncology
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
85.82%
PURPOSE: This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design. RESULTS: Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI...

Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein Kinase C(epsilon) regulates Ras/mitogen-activated protein kinase signaling and neuronal differentiation

Lonic, A.; Powell, J.; Kong, Y.; Thomas, D.; Holien, J.; Truong, N.; Parker, M.; Guthridge, M.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em //2013 EN
Relevância na Pesquisa
75.87%
The FGF receptors (FGFRs) control a multitude of cellular processes both during development and in the adult through the initiation of signaling cascades that regulate proliferation, survival, and differentiation. Although FGFR tyrosine phosphorylation and the recruitment of Src homology 2 domain proteins have been widely described, we have previously shown that FGFR is also phosphorylated on Ser779 in response to ligand and binds the 14-3-3 family of phosphoserine/threonine-binding adaptor/scaffold proteins. However, whether this receptor phosphoserine mode of signaling is able to regulate specific signaling pathways and biological responses is unclear. Using PC12 pheochromocytoma cells and primary mouse bone marrow stromal cells as models for growth factor-regulated neuronal differentiation, we show that Ser779 in the cytoplasmic domains of FGFR1 and FGFR2 is required for the sustained activation of Ras and ERK but not for other FGFR phosphotyrosine pathways. The regulation of Ras and ERK signaling by Ser779 was critical not only for neuronal differentiation but also for cell survival under limiting growth factor concentrations. PKCϵ can phosphorylate Ser779 in vitro, whereas overexpression of PKCϵ results in constitutive Ser779 phosphorylation and enhanced PC12 cell differentiation. Furthermore...

Novel fibroblast growth factor receptor signalling pathways regulating neuronal differentiation.

Kong, Yang
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2014
Relevância na Pesquisa
85.85%
The fibroblast growth factors (FGFs) consist of a family of growth factors that regulate diverse (or pleiotropic) responses, such as cell survival, proliferation, differentiation, and migration in both development and adulthood. The FGFs exert their biological activities through the binding and activation of four structurally related FGF receptors (FGFR1-4). The activation of FGFRs leads to FGFR tyrosine phosphorylation and the recruitment of SH2/PTB-domain signalling proteins, which are essential for initiating the downstream signalling pathways. Although receptor tyrosine phosphorylation is known to be important for cellular responses mediated by FGFRs, the precise mechanisms by which the FGFRs regulate pleiotropic biological responses remain unclear. In addition to receptor tyrosine phosphorylation, previous work in the Cell Growth and Differentiation Laboratory has shown that the FGFR cytoplasmic domain is also phosphorylated on a specific serine residue, Serine 779(S779), which recruits and binds the 14-3-3 family of phosphoserine/threonine-binding adaptor/scaffold proteins. However the precise role of the receptor phosphoserine signalling event in regulating downstream pathways and biological events has remained unclear. Using PC12 pheochromocytoma cells and primary mouse bone marrow stromal cells (BMSCs) as models for growth factor-regulated neuronal differentiation...

Co-Inhibition von epidermal growth factor receptor (EGFR) und insulin-like growth factor-I receptor (IGF-IR): Ein neuer Ansatz für die Reduktion der Zelltodresistenz humaner maligner Gliomzellen; Co-inhibition of epidermal growth factor receptor and type 1 insulin-like growth factor receptor: a new approach in reducing of restistance to apoptosis of human malignant glioma cells

Eisenmann, Christine
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
DE_DE
Relevância na Pesquisa
95.94%
In der vorliegenden Arbeit wurde zunächst der Effekt der Wachstumsfaktoren EGF, IGF-I, FGF-I und PDGF auf Wachstum und Überleben von zwölf humanen malignen Glioblastomzellinien bei Serumentzug untersucht. Dabei wurden bei den einzelnen Zelllinien unterschiedliche Abhängigkeit von individuellen Wachstumsfaktoren beobachtet, die als eine Art 'molekulare Signatur' Hinweise auf die Relevanz der zugehörigen Rezeptortyrosinkinase gelten können. Die Charakterisierung der Effekte einer Co-Inhibition von EGFR und IGF-IR auf den CD95L-induzierten Zelltod war der zentrale Bestandteil dieser Arbeit. Dabei konnte zunächst eine synergistische Sensitivierung gegenüber CD95 durch die Co-Inhibition bei den p53-Wildtyp-Zelllinien LNT-229 und U87MG nachgewiesen werden, nicht jedoch bei den p53-mutanten Zelllinien LN-18 und T98G. Experimente mit dem temperatursensitiven p53val135A zeigten jedoch, dass der sensitivierende Effekt der Co-Inhibition nicht p53-abhängig ist. Der Typ des durch die Co-Inhibition fazilitierten Zelltods war apoptotisch und begleitet von einer crmA-sensitiven Aktivierung von Caspase 8, den Effektorcaspasen 3 und 7, und dem Caspasesubstrat PARP. Da ein Effekt der Co-Inhibition auf das Expressionsniveau von CD95 ausgeschlossen wurde...

A vascular endothelial growth factor receptor-2 kinase inhibitor potentiates the activity of the conventional chemotherapeutic agents paclitaxel and doxorubicin in tumor xenograft models.

Emanuel, S.; Gruninger, R.; Fuentas, P.; Connolly, P.; Seamon, J.; Hazel, S.; Tominovich, R.; Hollister, B.; Napier, C.; D'Andrea, M.; Reuman, M.; Bignan, G.; Tuman, R.; Johnson, D.; Moffatt, D.; Batchelor, M.; Foley, A.; O'Connell, J.; Allen, R.; Perry,
Fonte: Amer Soc Pharmacology Experimental Therapeutics Publicador: Amer Soc Pharmacology Experimental Therapeutics
Tipo: Artigo de Revista Científica
Publicado em //2004 EN
Relevância na Pesquisa
95.89%
Inhibition of angiogenesis may have wide use in the treatment of cancer; however, this approach alone will not cause tumor regression but may only slow the growth of solid tumors. The clinical potential of antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the vascular endothelial growth factor receptor-2 (VEGF-R2) and other tyrosine kinases involved in angiogenesis, such as platelet-derived growth factor receptor, fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other kinase families. At nanomolar levels, JNJ-17029259 blocks VEGF-stimulated mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 µM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects. JNJ-17029259 delays the growth of a wide range of human tumor xenografts in nude mice when administered orally as single-agent therapy. Histological examination revealed that the tumors have evidence of reduced vascularity after treatment. In addition...

Tumor necrosis factor-astimulated membrane type 1-matrix metalloproteinase production is modulated by epidermal growth factor receptor signaling in human gingival fibroblasts

González Burgos, María Julieta; Guerrero, J.; Tobar, N.; Martínez Winkler, Jorge; Cáceres, M.; Smith, P. C.
Fonte: Blackwell Munksgaard Publicador: Blackwell Munksgaard
Tipo: Artículo de revista
EN
Relevância na Pesquisa
95.85%
Membrane type 1-matrix metalloproteinase (MT1- MMP) is a collagenolytic enzyme involved in connective tissue remodeling. In periodontal tissues, either cytokines or growth factors regulate the production of proteolytic enzymes. Mice deficient in epidermal growth factor receptor (EGFR) show a reduced expression of MT1-MMP, suggesting that this receptor may play an important role in MT1-MMP production. The present study evaluated the role of the inflammatory cytokine tumor necrosis factor-a (TNF-a) and EGFR in the production of MT1-MMP in gingival fibroblasts.

Activation of endogenous thrombin receptors causes clustering and sensitization of epidermal growth factor receptors of Swiss 3T3 cells without transactivation

Crouch, Michael F; Davy, Deborah; Willard, Francis; Berven, Leise
Fonte: Rockefeller University Press Publicador: Rockefeller University Press
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
75.86%
The G protein-coupled thrombin receptor can induce cellular responses in some systems by transactivating the epidermal growth factor (EGF) receptor. This is in part due to the stimulation of ectoproteases that generate EGF receptor ligands. We show here t

Insulin induces epidermal growth factor EGF receptor clustering and potentiates EGF-stimulated DNA synthesis in Swiss 3T3 cells: A mechanism for costimulation in mitogenic synergy

Crouch, Michael F; Davy, Deborah; Willard, Francis; Berven, Leise
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
75.9%
In many cellular systems, activation with more than one ligand can produce a cellular response that is greater than the sum of the individual responses to the ligands. This synergy is sometimes referred to as coactivation. In Swiss 3T3 fibroblasts, activation of the epidermal growth factor (EGF) receptor produces a weak induction of DNA synthesis. Insulin has no stimulatory effect on this response. However, in combination, EGF and insulin synergize to cause a large induction of S phase. The underlying cellular biochemistry of this effect has been examined. The data indicate that phospholipase C activation is a major component of agonist-induced DNA synthesis. In contrast, activation of p70 S6 kinase by single agonists was inversely related to their ability to stimulate DNA synthesis. Therefore, it was examined whether stimulation of Swiss 3T3 cells with insulin causes changes in the subcellular distribution of EGF receptors and phospholipase Cγ1 that could potentially explain the observed I synergy or costimulation. It was found that insulin effectively induced the accumulation of EGF receptors on the actin arc of cells without activation of the EGF receptor. In contrast, EGF, when added for several hours, did not cause accumulation of the EGF receptor at this site. However...