• Molecules and Cells
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• 제45권11호
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• pp.789-791
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• 2022

Targeting fibroblast growth factor receptors (FGFRs) has been slow compared to other targeted cancer therapies for receptor tyrosine kinases, such as epidermal growth factor receptors. The low efficacy and variable response have limited the growth of FGFR inhibitors in clinical use. Nevertheless, recent systematic and genomic approaches have identified the biological conditions for effectively targeting FGFRs and can accelerate the development of targeted drugs. Under clinical and preclinical trials, the inhibitors started fast growing furious races to target FGFRs. Finally, FGFRs will be more actionable and targetable with more precise and effective drugs at the end of the race, passing the finish line.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제28권6호
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• pp.549-558
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• 2006

During distraction osteogenesis, the angiogenic activity is crucial factor in the new bone formation. The aim of this study was to detect the autocrine growth activity in the cellular components of the distracted periosteum with observation of the expression of vascular endothelial growth factor (VEGF) and its receptors following the mandibular distraction osteogenesis. Unilateral mandibular distraction (0.5 mm twice per day for 10 days) was performed in six mongrel dogs. Two animals were sacrificed at 7, 14, and 28 days after completion of distraction, respectively. The distracted lingual periosteum was harvested and processed for immunohistochemical examinations. After then, we observed the expression of VEGF, Flt-1 (VEGFR-1), and Flk-1 (VEGFR-2) in the osteoblasts and immature mesenchymal cells of the distracted periosteum. At 7 days after distraction, the expression of VEGF and its receptors were significantly increased in the cellular components of the distracted periosteum. Up to 14 days following distraction, the increased expressions were maintained in the osteoblastic cells. At 28 days after distraction, the expression of VEGF and its receptors decreased, but VEGF was still expressed weak or moderate in the osteoblastic cells of distracted periosteum. The expression pattern of VEGF and its receptors shown here suggested that VEGF play an important role in the osteogenesis, and these osteoblastic cell-derived VEGF might act as autocrine growth factor during distraction osteogenesis. In the other word, the cellular components in the distracted periosteum, such as osteoblasts and immature mesenchymal cells, might have autocrine growth activity during distraction osteogenesis.

• BMB Reports
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• 제44권3호
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• pp.182-186
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• 2011

Exogenous stimuli such as nerve growth factor (NGF) exert their effects on neurite outgrowth via Trk neurotrophin receptors. TrkA receptors are known to be ubiquitinated via proteasome inhibition in the presence of NGF. However, the effect of proteasome inhibition on neurite outgrowth has not been studied extensively. To clarify these issues, we investigated signaling events in PC12 cells treated with NGF and the proteasome inhibitor MG132. We found that MG132 facilitated NGF-induced neurite outgrowth and potentiated the phosphorylation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways and TrkA receptors. MG132 stimulated internalization of surface TrkA receptor and stabilized intracellular TrkA receptor, and the $Ub^{K63}$ chain was found to be essential for stability. These results indicate that the ubiquitin-proteasome system potentiated neurite formation by regulating the stability of TrkA receptors.

• 대한의생명과학회지
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• 제11권2호
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• pp.175-183
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• 2005

The two major isoflavones in soy, genistein and daidzein, are well known to prevent hormone-dependent cancers by their anti estrogenic activity. The exact molecular mechanisms for the protective action are, however, not provided yet. It has been reported that genistein and daidzein have a potential anticancer activity through their antiproliferative effect in many hormone-dependent cancer cell lines. Transforming growth $factor-\beta1(TGF-\beta1)$ has also been found to have cell growth inhibitory effect, especially in mammary epithelial cells. This knowledge led to a hypothetical mechanism that the soy isoflavones-induced growth inhibitory effect can be derived from the regulation of $TGF-\beta1$ and $TGF-\beta$ receptors. In order to test this hypothesis, the effects of the soy isoflavones at various concentrations and periods on the expression of $TGF-\beta1$and $TGF-\beta$ receptors were investigated by using Northern blot analysis in human breast carcinoma epithelial cell lines, an estrogen receptor positive cell line (MCF-7) and an estrogen receptor negative cell line (MDA-MB-231). As a result, only genistein has shown a profound dose-dependent effect on $TGF-\beta1$ expression in the $ER^+$ cell line within the range of doses tested, and the expression levels are correspondent to their inhibitory activities of cell growth. Moreover, daidzein showed down-regulated $TGF-\beta1$ expression at a low dose, the cell growth proliferation was promoted at the same condition. Therefore, antiproliferative activity of the soy isoflavones can be mediated by $TGF-\beta1$ expression, and the effects are mainly, if not all, occurred by ER dependent pathway. The expression of $TGF-\beta$ receptors was induced at a lower dose than the one for $TGF-{\beta}1$ induction regardless of the presence of ER, and the expression patterns are similar to those of the cell growth inhibition. These results indicated that the regulation of $TGF-\beta$ receptor expression as well, prior to $TGF-\beta1$ expression, may be involved in the antiproliferative activity of soy isoflavones. Little or no expression of $TGF-\beta$ receptors was found in the MCF-7 and MDA-MB-231 cells, suggesting refractory properties of the cells to growth inhibitory effect of the $TGF-\beta$. The soy isoflavones can seemingly restore the sensitivity of growth inhibitory responses to $TGF-\beta1$ by re-inducing $TGF-\beta$ receptors expression. In conclusions, our findings presented in this study show that the antitumorigenic activity of the soy isoflavones could be mediated by not only $TGF-\beta1$induction but $TGF-\beta$ receptor restoration. Thus, soy isoflavones could be good model molecules to develop new nonsteroidal antiestrogenic chemopreventive agents, associated with, regulation of $TGF-\beta$ and its receptors.

• Journal of Periodontal and Implant Science
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• 제25권3호
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• pp.518-528
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• 1995

The immunohistochemical study has been performed on the distribution of receptors for various growth factors in the newly forming granulation tissues following the guided tissue regeneration procedures. Two specimens from 2 different patients were collected from the newly forming granulation tissues at 2 weeks following GTR procedures using Gore-tex menbrane and rubber dam, respectively. For immunohistochemical localization of each recptor, anti-platelet-derived growth factor $receptor-{\alpha}$, anti-platelet-derived growth factor $receptor-{\beta}$. anti-insulin-like growth factor receptor, anti-basic fibroblast growth factor receptor, anti-transforming growth $factor-{\beta}$ receptor and anti-fibronectin receptor were incubated onto the specimens as primary antibodies. After the reaction, FITC-conjugated second antibodies have been applied. When the total numbers of immunoreactive cells and the true positive cells were counted, there were high variability among receptors tested in the present study. The mean number of immunoreactive cells were highest in the case for anti-IFG-1 receptor. However the number of true positive cells were highest in the case for $TGF-{\beta}$ receptor. The present investigation indicated that the receptor for $TGF-{\beta}$ were stongly expressed in the newly forming granulation tissues following the guided tissue regeneration therapy.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제35권5호
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• pp.287-293
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• 2009

Cell survival is the result of a balance between programmed cell death and cellular proliferation. Cell membrane receptors and their associated signal transducing proteins control these processes. Of the numerous receptors and signaling proteins, epidermal growth factor receptor (EGFR) is one of the most important receptors involved in signaling pathways implicated in the proliferation and survival of cancer cells. EGFR is often highly expressed in human tumors including oral squamous cell carcinomas, and there is increasing evidence that high expression of EGFR is correlated with poor clinical outcome of common human cancers. Therefore, we examined the antiproliferative activity of gefitinib, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), in head and neck cancer cell lines. SCC-9, KB cells were cultured and growth inhibition activity of gefitinib was measured with MTT assay. To study influence of gefitinib in cell cycle, we performed cell cycle analysis with flow cytometry. Western blot was done to elucidate the expression of EGFR in cell lines and phosphorylation of EGFR and downstream kinase protein, Erk and Akt. Significant growth inhibition was observed in SCC-9 cells in contrast with KB cells. Also, flow cytometric analysis showed G1 phase arrest only in SCC-9 cells. In Western blot analysis for investigation of EGFR expression and downstream molecule phosphorylation, gefitinib suppressed phosphorylation of EGFR and downstream protein kinase Erk, Akt in SCC-9. However, in EGFR positive KB cells, weak expression of active form of Erk and Akt and no inhibitory activity of phosphorylation in Erk and Akt was observed. The antiproliferative activity of gefitinib was not correlated with EGFR expression and some possibility of phosphorylation of Erk and Akt as a predictive factor of gefitinib response was emerged. Further investigations on more reliable predictive factor indicating gefitinib response are awaited to be useful gefitinib treatment in head and neck cancer patients.

• Journal of Microbiology and Biotechnology
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• 제12권2호
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• pp.249-257
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• 2002

Pseudomonas fluorescens GL20 is a plant growth-promoting rhizobacterium that produces a large amount of hydroxamate siderophore under iron-limited conditions. The strain GL20 considerably inhibited the spore germination and hyphal growth of a plant pathogenic fungus, Fusarium solani, when iron was limited, significantly suppressed the root-rot disease on beans caused by F. solani, and enhanced the plant growth. The mechanism for the beneficial effect of strain GL20 on the disease suppression was due to the siderophore production, evidenced by mutant strains derived from the strain. Analysis of the outer membrane protein profile revealed that the growth of strain GL20 induced the synthesis of specific iron-regulated outer membrane proteins with molecular masses of 85- and 90 kDa as the high-affinity receptors for the ferric siderophore. In addition, a cross-feeding assay revealed the presence of multiple inducible receptors for heterologous siderophores in the strain. In order to induce increased efficacy and potential in biological control of plant disease, a siderophore-overproducing mutant, GL20-S207, was prepared by NTG mutagenesis. The mutant GL20-S207 produced nearly 2.3 times more siderophore than the parent strain. In pot trials of beans with F. solani, the mutant increased plant growth up to 1.5 times compared with that of the parent strain. These results suggest that the plant growth-promoting P. fluorescens GL20 and the genetically bred P. fluorescens GL20-S207 can play an important role in the biological control of soil-borne plant diseases in the rhizosphere.

• 대한핵의학회지
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• 제36권1호
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• pp.8-18
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• 2002

Early and accurate diagnosis of tumors using positron omission tomography (PET) has been the focus of considerable interest due to its high metastasis and mortality rates at late detection. PET radiopharmaceuticals-which exhibit a high tumor-to-background uptake ratio, and appropriate metabolic characteristics, and pharmacokinetics-are attractive tools for tumor imaging. Tumor imaging by these radiopharmaceuticals are based on metabolic and receptor imaging. The former is based on accelerated metabolism in tumor tissue compared to normal tissue and the rate roughly corresponding to the rate of growth of tumors. Radiopharmaceuticals for this purpose include radiolabeled sugars, amino acids, and nucleosides which detect increased glucose utilization, protein synthesis, and DNA synthesis, respectively. Tumor receptor imaging is based on the proliferation of tumor cells regulated by many hormones and growth factors, which bind to the corresponding receptors and exhibit the biological responses Radiopharmaceuticals used to image the tumor receptor systems may be ligands for the specific receptors and antibodies for the growth factor receptors. Some antitumor agents have been labeled with radionuclides and used to study in vivo biodistribution and pharmacokinetics in humans. This overview describes typical PET radiopharmaceuticals used for tumor imaging based on their uptake mechanisms.

• 대한불안의학회지
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• 제1권1호
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• pp.25-30
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• 2005

In the 40 years since the first benzodiazepine was brought into clinical use there has been a substantial growth in understanding the molecular basis of action of these drugs and the role of their receptors in anxiety disorders. Benzodiazepine receptors are present throughout the brain with the highest concentration in cortex, and it potentiate and prolong the synaptic action of the inhibitory neurotransmitter GABA. Central benzodiazepine receptors and $GABA_A$ receptors are part of the same macromolecular complex. Abnormalities of these $GABA_A$-benzodiazepine receptors as a result of drug challenge tests and neuroimaging studies may underlie some anxiety disorders. The role of $GABA_A$-benzodiazepine receptors in the action of benzodiazepine and as a factor in anxiety disorder, in both animal and humans including knock-out and knock in technique, may lead to new anxiolytics that have potentially significant therapeutic gains without unwanted side effects.

• BMB Reports
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• 제43권5호
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• pp.311-318
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• 2010

This review explored the mechanism of breast carcinoma progression by focusing on integrins and receptor tyrosine kinases (or growth factor receptors). While the primary role of integrins was previously thought to be solely as mediators of adhesive interactions between cells and extracellular matrices, it is now believed that integrins also regulate signaling pathways that control cancer cell growth, survival, and invasion. A large body of evidence suggests that the cooperation between integrin and receptor tyrosine kinase signaling regulates certain signaling functions that are important for cancer progression. Recent developments on the crosstalk between integrins and receptor tyrosine kinases, and its implication in mammary tumor progression, are discussed.