• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8633-8636
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• 2016

Background: To investigate the expression of insulin-like growth factor-I receptor (IGF-IR) and sushi domain containing protein 3 (SUSD3) in breast cancer tissue, and analyze their relationship with clinical parameters and the correlation between the two proteins. Materials and Methods: The expression of IGF-IR and SUSD3 in 100 cases of breast cancer tissues and adjacent normal breast tissues after surgery was detected by immunohistochemical technique MaxVisionTM, and the relationship with clinical pathological features was further analyzed. Results: The positive rate of IGF-IR protein was 86.0% in breast cancer, higher than 3.0% in adjacent normal breast tissue (P<0.05). The positive expression rate of SUSD3 protein was 78.0% in breast cancer, higher than 2.0% in adjacent normal breast tissue (P<0.05). The expression of IGF-IR and SUSD3 was related to estrogen receptor and pathological types (P<0.05),but not with age, stage, the expression of HER-2 and Ki-67 (P>0. 05). The expression of IGF-IR and SUSD3 in breast cancer tissue was positively related (r=0.553, P<0.01). Conclusions: The expression of IGF-IR and SUSD3 may be correlated to the occurrence and development of breast cancer. The combined detection of IGF-IR, SUSD3 and ER may play an important role in judging prognosis and guiding adjuvant therapy after surgery of breast cancer.

• BMB Reports
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• v.49 no.8
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• pp.414-423
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• 2016

MG53 is a member of the TRIM-family protein that acts as a key component of the cell membrane repair machinery. MG53 is also an E3-ligase that ubiquinates insulin receptor substrate-1 and controls insulin signaling in skeletal muscle cells. Since its discovery in 2009, research efforts have been devoted to translate this basic discovery into clinical applications in human degenerative and metabolic diseases. This review article highlights the dual function of MG53 in cell membrane repair and insulin signaling, the mechanism that underlies the control of MG53 function, and the therapeutic value of targeting MG53 function in regenerative medicine.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.397-405
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• 2001

The ryanodine receptor, a $Ca^{2+}$ release channel of the sarcoplasmic reticulum (SR), is responsible for the rapid release of $Ca^{2+}$ that activates cardiac muscle contraction. In the excitation-contraction coupling cascade, activation of SR $Ca^{2+}$ release channel is initiated by the activity of sarcolemmal $Ca^{2+}$ channels, the dihydropyridine receptors. Previous study showed that the relaxation defect of diabetic heart was due to the changes of the expressional levels of SR $Ca^{2+}$ATPase and phospholamban. In the diabetic heart contractile abnormalities were also observed, and one of the mechanisms for these changes could include alterations in the expression and/or activity levels of various $Ca^{2+}$ regulatory proteins involving cardiac contraction. In the present study, underlying mechanisms for the functional derangement of the diabetic cardiomyopathy were investigated with respect to ryanodine receptor, and dihydropyridine receptor at the transcriptional and translational levels. Quantitative changes of ryanodine receptors and the dihydropyridine receptors, and the functional consequences of those changes in diabetic heart were investigated. The levels of protein and mRNA of the ryanodine receptor in diabetic rats were comparable to these of the control. However, the binding capacity of ryanodine was significantly decreased in diabetic rat hearts. Furthermore, the reduction in the binding capacity of ryanodine receptor was completely restored by insulin. This result suggests that there were no transcriptional and translational changes but functional changes, such as conformational changes of the $Ca^{2+}$ release channel, which might be regulated by insulin. The protein level of the dihydropyridine receptor and the binding capacity of nitrendipine in the sarcolemmal membranes of diabetic rats were not different as compared to these of the control. In conclusion, in diabetic hearts, $Ca^{2+}$ release processes are impaired, which are likely to lead to functional derangement of contraction of heart. This dysregulation of intracellular $Ca^{2+}$ concentration could explain for clinical findings of diabetic cardiomyopathy and provide the scientific basis for more effective treatments of diabetic patients. In view of these results, insulin may be involved in the control of intracellular $Ca^{2+}$ in the cardiomyocyte via unknown mechanism, which needs further study.

• BMB Reports
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• v.32 no.2
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• pp.196-202
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• 1999

The existence of the Ras-independent signal transduction pathway of insulin leading to DNA synthesis was investigated in Rat-1 fibroblasts overexpressing human insulin receptor (HIRc-B) using the single-cell microinjection technique. Microinjection of a dominant-negative mutant $Ras^{N17}$ protein into quiescent HIRc-B cells inhibited the DNA synthesis stimulated by insulin. Microinjection of oncogenic H-$Ras^{V12}$ protein ($H-Ras^{V12}$) (0.1 mg/ml) induced DNA synthesis by 35%, whereas that of control-injected IgG was induced by 20%. When the marginal amount of oncogenic H-$Ras^{V12}$ protein was coinjected with a dominant-negative mutant of the H-Ras protein ($Ras^{N17}$), DNA synthesis was 35% and 74% in the absence and presence of insulin, respectively. This full recovery of DNA synthesis by insulin suggests the existence of the Ras-independent pathway. The same recovery was observed in the cells coinjected with either H-$Ras^{V12}$ plus H-$Ras^{N17}$ plus SH2 domain of the p85 subunit of PI3-kinase ($p85^{SH2-N}$) or H-$Ras^{V12}$ plus H-$Ras^{N17}$ plus interfering anti-Shc antibody. When co-injected with a dominant-negative H-$Ras^{N17}$, the DNA synthesis induced by the Ras-independent pathway was blocked. These results indicate that the Ras-independent pathway of insulin leading to DNA synthesis exists, bypassing the p85 of PI3-kinase and Shc protein, and requires Rac1 protein.

• Tuberculosis and Respiratory Diseases
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• v.67 no.1
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• pp.8-13
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• 2009

Background: The insulin receptor substrate-1 (IRS-1) is the primary docking molecule for the insulin-like growth factor I receptor (IGF-IR), and is required for activation of the phosphatidylinositol 3'-kinase (PI3K) pathway. IRS-1 activation of the (PI3K) pathway regulates IGF-mediated survival, enhancement of cellular motility and apoptosis. Therefore, we attempted to ascertain whether IRS-1 genetic variations affect an individual's risk for non-small cell lung cancer (NSCLC). Methods: Two-hundred and eighteen subjects, either diagnosed with NSCLC or control subjects, were matched by age, gender and smoking status. Genomic DNA from each subject was amplified by PCR and analyzed according to the restriction fragment length polymorphism (RFLP) profile to detect the IRS-1 G972R polymorphism. Results: The frequencies of each polymorphic variation, in the control population, were as follows: GG=103 (94.5%) and GR=6 (5.5%); for the NSCLC subjects, the genotypic frequencies were as follows: GG=106 (97.2%) and GR=3 (2.8%). We could not demonstrate statistically significant differences in the genotypic distribution between the NSCLC and the control subjects (p=0.499, Fisher's Exact test). The relative risk of NSCLC, associated with the IRS-1 G972R polymorphic variation, was 1.028 (95% CI; 0.63~9.90). In addition, we found no differences between polymorphic variants with regard to the histological subtype of NSCLC. Conclusion: We did not observe any noteworthy differences in the frequency of the IRS-1 G972R polymorphism in NSCLC patients, compared to control subjects. These results suggest suggesting that, in our study population, the IRS-1 G972R polymorphism does may not appear to be associated with an increased risk of NSCLC.

• Journal of Life Science
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• v.17 no.1 s.81
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• pp.56-63
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• 2007

Insulin stimulates the fusion of intracellular vesicles containing glucose transporter 4 (GLUT4) with plasma membrane in adipocytes and muscle cells. Here we show that adipocyte differentiation results in enhanced insulin sensitivity of glucose uptake. On the other hand, glucose uptake in response to platelet-derived growth factor (PDGF) stimulation was markedly reduced by adipocyte differentiation. Expression level of insulin receptor and caveolin-1 was dramatically increased during adipocyte differentiation. Adipocyte differentiation caused :ilightly enhanced activation of acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) by insulin stimulation. However, activation of Akt by PDGF stimulation was largely reduced. Activation of ERK was not detected in both fibroblasts and adipocytes after stimulation with insulin. PDGF-dependent activation of ERK was reduced by adipocyte differentiation. Insulin-dependent glucose uptake was abrogated by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, in both fibroblasts and adipocytes. Also disassembly of caveolae structure by $methyl-\beta-cyclodextrin$ caused impairment of Akt activation and glucose uptake. Finally, insulin receptor, Akt, SH2-domain-containing inositol 5-phosphatase 2 (SHIP2), and regulatory subunit of PI3K are localized at lipid raft domain and the translocation was facilitated upon insulin stimulation. Given these results, we suggest that lipid raft provide proper site for insulin action for glucose uptake.

• Journal of the Korean Society of Food Science and Nutrition
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• v.32 no.3
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• pp.437-443
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• 2003

Epidemiological data suggest that lycopene has anticancer activities in humans. Insulin-like growth factor-I receptor (IGF-IR) is a transmembrane tyrosine kinase that mediates the biological actions of IGFs and may play an active role in cancer progression. Because our previous in vitro studies have indicated lycopene inhibits HT-29 cell growth, the aim of this study was to determine whether lycopene induces apoptotic cell death and the inhibitory effect of lycopene on HT-29 cell growth is related to changes in IGF-IR levels and the receptor's intracellular signalling pathways. HT-29 cells were incubated for 4 days in serum-free medium in the presence of 0, 25, 50, or 100 $\mu$M lycopene, and the DNA fragmentation assay was performed. Cells treated with lycopene produced a distinct oligonucleosomal ladder with different sizes of DNA fragments, a typical characteristic of cells undergoing apoptosis. HT-29 cells were cultured for 4 days in serum-free medium in the presence of 0~100 $\mu$M lycopene and IGF-I (10nM) was added for 0~60 minutes immediately prior to lysate preparations. Western blot analysis of total lysates revealed that lycopene decreased the levels of IRS-1, Akt, phosphatidylinositol 3-kinase (PI3K), and IGF-IR $\beta$-subunit, and increased the levels of the IGF-IR precursor dose dependently. Lycopene also decreased IGF-I-induced phosphorylation of IGF-IR$\beta$, IRS-1 and Akt, which were, at least in part, due to decreased expression of these proteins. These results suggest that lycopene induces apoptosis of HT-29 cells by inhibiting IGF-IR signaling thereby interfering with an IGF-II-driven autocrine growth loop, which is known to exist in this cell line.

• Molecules and Cells
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• v.47 no.3
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• pp.100007.1-100007.11
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• 2024

Recent evidence establishes a pivotal role for obesity-induced inflammation in precipitating insulin resistance and type-2 diabetes. Central to this process is the proinflammatory M1 adipose-tissue macrophages (ATMs) in epididymal white adipose tissue (eWAT). Notably, natural killer (NK) cells are a crucial regulator of ATMs since their cytokines induce ATM recruitment and M1 polarization. The importance of NK cells is shown by the strong increase in NK-cell numbers in eWAT, and by studies showing that removing and expanding NK cells respectively improve and worsen obesity-induced insulin resistance. It has been suggested that NK cells are activated by unknown ligands on obesity-stressed adipocytes that bind to NKp46 (encoded by Ncr1), which is an activating NK-cell receptor. This was supported by a study showing that NKp46-knockout mice have improved obesity-induced inflammation/insulin resistance. We therefore planned to use the NKp46-knockout mice to further elucidate the molecular mechanism by which NKp46 mediates eWAT NK-cell activation in obesity. We confirmed that obesity increased eWAT NKp46⁺ NK-cell numbers and NKp46 expression in wild-type mice and that NKp46-knockout ablated these responses. Unexpectedly, however, NKp46-knockout mice demonstrated insulin resistance similar to wild-type mice, as shown by fasting blood glucose/insulin levels and glucose/insulin tolerance tests. Obesityinduced increases in eWAT ATM numbers and proinflammatory gene expression were also similar. Thus, contrary to previously published results, NKp46 does not regulate obesity-induced insulin resistance. It is therefore unclear whether NKp46 participates in the development of obesity-induced inflammation and insulin resistance. This should be considered when elucidating the obesity-mediated molecular mechanisms that activate NK cells.

• BMB Reports
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• v.33 no.2
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• pp.120-125
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• 2000

M2PI is an active single chain mini-proinsulin with a 9-residue linker containing the turn-forming sequence 'YPGDV' between the B- and A-chains, but which retains about 50% of native insulin receptor binding activity. The refolding efficiency of M2PI is higher than proinsulin by 20-40% at alkaline pH, and native insulin is generated by the enzymatic conversion of M2PI. The solution structure of M2PI was determined by NMR spectroscopy. The global structure of M2PI is similar to that of native insulin, but the flexible linker between the B- and A-chains perturbed the N-terminal A-chain and C-terminal B-chain. The helix in the N-terminal A-chain is partly perturbed and the ${\beta}$-turn in the B-chain is disrupted in M2PI. However, the linker between the two chains was completely disordered indicating that the designed turn was not formed under the experimental conditions (20% acetic acid). Considering the fact that an insulin analogue, directly cross-linked between the C-terminus of the B-chain and the N-terminus of the A-chain, has negligible binding activity, a flexible linker between the two chains is sufficient to keep binding activity of M2PI, but the perturbed secondary structures are detrimental to receptor binding.

• Development and Reproduction
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• v.26 no.4
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• pp.165-174
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• 2022

Three proteins [myosin heavy chain (MHC), filamin-C fragment (FIL-C), and actin 2 (ACT2)] were identified in adductor muscle from diploid and triploid Pacific oysters (Crassostrea gigas) and the relationship between the condition index (CI) and mRNA expression of these genes was investigated, together with the mRNA expression of molluscan insulin-related peptide (MIP), C. gigas insulin receptor-related receptor (CIR), and insulin-like growth factor binding protein complex acid labile subunit (IGFBP-ALS). Monthly changes in the CI were similar to the changes in the tissue weight rate in both groups. ACT2 and MHC mRNA expression was statistically higher in the triploid than the diploid, while FIL-C mRNA expression was significantly higher in the diploid (p<0.05). The MIP, CIR, and IGFBP-ALS mRNA expression of the diploid oysters were all significantly higher in July than in other months (p<0.05). The MIP, CIR, and IGFBP-ALS mRNA expression in the triploid oysters was high in July, but there were no significant differences (p>0.05). Changes in the expression levels of the genes investigated in this study could be used as intrinsic indicators of the annual growth, maturity, and spawning period of cultured diploid and triploid C. gigas in Tongyeong, Korea.