• Molecules and Cells
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• 제28권6호
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• pp.589-593
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• 2009

In this study, the roles of the p38 MAPK, ERK1/2 and JNK signaling pathway in IGF-I-induced AR induction and activation were examined. C2C12 cells were treated with IGF-I in the absence or presence of various inhibitors of p38 MAPK (SB203580), ERK1/2 (PD98059), and JNK (SP600125). Inhibition of the MAPK pathway with SB203580, PD98059, or SP600125 significantly decreased IGF-I-induced AR phosphorylation and total AR protein expression. IGF-I-induced nuclear fraction of total AR and phosphorylated AR were significantly inhibited by SB203580, PD98059, or SP600125. Furthermore, IGF-I-induced AR mRNA and skeletal ${\alpha}-actin$ mRNA were blocked by those inhibitors in dose-dependent manner. Confocal images showed that IGF-I-induced AR nuclear translocation from cytosol was significantly blocked by SB203580, PD98059, or SP600125, suggesting that the MAPK pathway regulates IGF-I-induced AR nuclear localization in skeletal muscle cells. The present results suggest that the MAPK pathways are required for the ligand-independent activation of AR by IGF-I in C2C12 skeletal muscle cells.

• Journal of mucopolysaccharidosis and rare diseases
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• 제1권2호
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• pp.54-59
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• 2015

Purpose: Growth hormone (GH) therapy substantially improves several cognitive functions in PWS. However, the molecular mechanisms underlying the beneficial effects of GH on cognition remain unclear in PWS. In this study, we investigated the effects of recombinant human GH on the gene expression of GABAB receptor subunits and GH/insulin-like growth factor (IGF) axis genes in the brain regions of PWS-mimicking mice (Snord116del). Methods: Snord116del mice were injected subcutaneously with 1.0 mg/kg GH or saline, once daily for 7 days. The collected brain tissues were analyzed for mRNA content using quantitative PCR (qPCR) in the cerebellum, hippocampus, and cerebral cortex. Results: GH increased the mRNA expression level of the $GABA_{B1}$ receptor subunit ($GABA_{BR1}$) and IGF-1R in the cerebellum. Furthermore, a significant positive correlation was found between the level of $GABA_{BR1}$ mRNA and the expression of the IGF-1R transcript. GH also induced an increase in the mRNA expression of IGF-2 and IGF-2R in the cerebellum. Conclusion: These data indicate that GH may provide beneficial effects on cognitive function through its influences on the expression of $GABA_{BR1}$ and GH/IGF-1 axis genes in PWS patients.

• 생명과학회지
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• 제28권2호
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• pp.265-273
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• 2018

에스트로겐(E2)은 유방암의 발달과 진행에 관여하며, 에스트로겐 수용체(ER)에 의해 매개된다. ER은 유방암세포에서 epidermal growth factor receptor와 insulin-like growth factor-1 receptor의 신호전달경로들 사이에서 다양한 cross-talk을 통하여 세포의 증식, 이주, 침습 및 약물에 대한 저항성을 일으키는데 중요한 역할을 수행한다. 유방암은 내분비신호전달의 항상성 붕괴에 의해 주로 발생되며, 특히 E2/IGF-1/EGF와 ER/G-protein estrogen receptor (GPER)/IGF-1R/EGFR, 그리고 이들의 세포내 신호전달 매개인자들의 통제되지 않는 발현과 활성증가에 의해 유발된다. 이러한 변화는 E2와 성장인자 신호전달 사이의 복잡한 cross-talk에 영향을 주어 결국 암의 진행과 내분비조절인자들에 대한 저항성을 갖게 된다. 따라서, E2와 성장인자들 사이의 cross-talk에 관한 분자적 기전을 단계별로 규명하는 것은 유방암의 다양한 유형에 따른 맞춤형 치료에 기여할 것으로 사료된다. 특히, 다양한 유전형 및 표현형을 가진 유방암의 치료를 위한 전략으로서, ER+ 호르몬의존성 유방암세포에 대한 aromatase 억제제 및 E2작용 차단제의 사용과 E2와 성장인자들 사이의 cross-talk에 의한 암세포의 증식억제를 위한 IGF-1R/EGFR 활성차단제의 사용 등을 들 수 있다. 뿐만 아니라, ER과 EGFR/IGF-1R 사이의 cross-talk에 의해 조절되는 ECM 분자들의 발현변화는 유방암세포의 전이에 대한 표적치료제를 위해 활용될 수 있다. 따라서, 암의 진행과 관련된 ER, GPER, IGF-1R 및 EGFR 매개에 의한 신호전달경로들 사이의 cross-talk에 관한 보다 더 자세한 분자적 수준의 규명이 필요할 것으로 사료된다.

• The Korean Journal of Physiology and Pharmacology
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• 제20권3호
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• pp.297-304
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• 2016

Klotho functions as a tumor suppressor predominantly expressed in renal tubular cells, the origin of clear cell renal cell carcinoma (ccRCC). Altered expression and/or activity of growth factor receptor have been implicated in ccRCC development. Although Klotho suppresses a tumor progression through growth factor receptor signaling including insulin-like growth factor-1 receptor (IGF-1R), the role of Klotho acting on IGF-1R in ccRCC and its clinical relevance remains obscure. Here, we show that Klotho is favorable prognostic factor for ccRCC and exerts tumor suppressive role for ccRCC through inhibiting IGF-1R signaling. Our data shows the following key findings. First, in tumor tissues, the level of Klotho and IGF-1R expression are low or high, respectively, compared to that of adjacent non-neoplastic parenchyma. Second, the Klotho expression is clearly low in higher grade of ccRCC and is closely associated with clinical outcomes in tumor progression. Third, Klotho suppresses IGF-1-stimulated cell proliferation and migration by inhibiting PI3K/Akt pathway. These results provide compelling evidence supporting that Klotho acting on IGF-1R signaling functions as tumor suppressor in ccRCC and suggest that Klotho is a potential carcinostatis substance for ccRCC.

• Archives of Pharmacal Research
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• 제27권4호
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• pp.361-370
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• 2004

The discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades is a key step to understanding insulin and insulin-like growth factor (IGF) action. Moreover, IRS-proteins coordinate signals from the insulin and IGF receptor tyrosine kinases with those generated by proinflammatory cytokines and nutrients. The IRS2-branch of the insulin/IGF signaling cascade has an important role in both peripheral insulin response and pancreatic $\beta$-cell growth and function. Dysregulation of IRS2 signaling in mice causes the failure of compensatory hyperinsulinemia during peripheral insulin resistance. IRS protein signaling is down regulated by serine phosphorylation or protea-some-mediated degradation, which might be an important mechanism of insulin resistance during acute injury and infection, or chronic stress associated with aging or obesity. Under-standing the regulation and signaling by IRS1 and IRS2 in cell growth, metabolism and survival will reveal new strategies to prevent or cure diabetes and other metabolic diseases.

• Fisheries and Aquatic Sciences
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• 제18권4호
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• pp.417-420
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• 2015

We investigated the relationship between viability and IGF-1 receptor (IGF-1R) activity in D-shaped and umbo larvae of the surf clam Spisula sachalinensis after treatment with vitrification solution (VS) or freezing. In a toxicity assay, VS1, containing 5 M dimethyl sulfoxide (DMSO), was very harmful to D-shaped and umbo larvae. However, VS2, containing 5 M ethylene glycol (EG), was not harmful to either larval stage. Although VS2 had a promising toxicity test outcome, none of the larvae survived vitrification. After immersion into VSs and freezing, IGF-1R ${\beta}$-subunits were detected in all larvae; however, tyrosine phosphorylation of intracellular ${\beta}$-subunits was detected only in the control and live groups. These results suggest that activation of IGF-1R may influence surf clam larvae viability.

• BMB Reports
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• 제33권6호
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• pp.454-462
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• 2000

Interleukin-4(IL-4) is known to be a major cytokine regulating immunoglobulin E(IgE) response by the induction of IgE production and type II IgE receptor(IgER II: CD23) expression. Recently, however, the role of neuroendocrine factors has been implicated in modulating the IgE response. Among various neuroendocrine growth factors, we investigated the effects of the insulin-like growth factor-1(IGF-1) since IL-4 and IGF-1 share common intracellular signaling molecules, such as the insulin receptor substrate-1/2(IRS-1/2) to induce a specific cellular response. In the human peripheral blood mononuclear cell (PBMC) cultures, IGF-1 was capable of inducing a substantial level of IgE production in a dose-dependent manner. It also noticeably upregulated the IL-4-induced or IL-4 plus anti-CD40-induced IgE production. Similarly, the IGF-1-induced IgE production was enhanced by IL-4 or anti-CD40 in an additive manner, which became saturated at high concentrations of IGF-1. Although IGF-1 alone did not induce IgER II (CD23) expression, it augmented the IL-4-induced surface CD23 expression in a manner similar to the action of anti-CD40. These results imply that IGF-1 is likely to utilize common signaling pathways with IL-4 and anti-CD40 to induce IgE and IgER II expression. In support of this notion, we observed that IGF-1 enhanced the IL-4-induced signal transducers and activators of transcription 6(STAT6) activation and independently induced $NF-{\kappa}B$ activation. Both of these bind to the IgE(C) or IgER II (CD23) promoters. Together, our data suggest that IL-4 and IGF-1 work cooperatively to activate STAT6 and $NF-{\kappa}B$. This leads to the subsequent binding of these transcription factors to the $C{\varepsilon}$ and CD23 promoters to enhance the expression of IgE and IgER II. The observed differential ability of IGF-1 on the induction of IgE vs. IgER II is discussed based on the different structure of the two promoters.

• BMB Reports
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• 제48권6호
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• pp.342-347
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• 2015

The expression of epidermal growth factor receptor (EGFR) is an important diagnostic marker for triple-negative breast cancer (TNBC) cells, which lack three hormonal receptors: estrogen and progesterone receptors as well as epidermal growth factor receptor 2. EGFR transactivation can cause drug resistance in many cancers including TNBC, but the mechanism underlying this phenomenon is poorly defined. Here, we demonstrate that insulin treatment induces EGFR activation by stimulating the interaction of EGFR with insulin-like growth factor receptor 1 (IGF-1R) in the MDA-MB-436 TNBC cell line. These cells express low levels of EGFR, while exhibiting high levels of IGF-1R expression and phosphorylation. Low-EGFRexpressing MDA-MB-436 cells show high sensitivity to insulinstimulated cell growth. Therefore, unexpectedly, insulin stimulation induced EGFR transactivation by regulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells. [BMB Reports 2015; 48(6): 342-347]

• Reproductive and Developmental Biology
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• 제30권2호
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• pp.93-97
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• 2006

To study the signaling effect of insulin-like growth factor-I(IGF-1), transgenic mice containing IGF-1 Receptor (IGF-1R) cDNA fused to metallothionein promoter were produced by DNA microinjection into the pronucleus of mouse zygote. Three founders were produced with transgenic mice containing IGF-1R gene. Transgenic mice lines contained approximately $4{\sim}20$ copies of transgenes per cell and transmission of this gene into the progeny with Mendelian manner were determined. The founder mice were mated with normal mice to produce $F_1$ mice and then $F_2$ mice. Transmission rates of IGF-1R transgene in the progeny mice were $25{\sim}60%$ in $F_1$ generation and $40{\sim}50%$ in $F_2$ generation. The mRNA expression of IGF-1R transgene in liver was analyzed using RT-PCR for IGF-1R gene in liver. When body weights of transgenic pups were measured during 4, 10 and 14 weeks after birth, IGF-1R transgenic mice grew faster than non transgenic littermates. This study indicated that growth regulation by IGF-1 signaling through IGF-1R can be elucidated using IGF-1R transgenic mice.

• 대한약리학회:학술대회논문집
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• 대한약리학회 2006년도 58th Annual Meeting of The Korean Society of Pharmacology
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• pp.58-58
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• 2006