• 대한임상검사과학회지
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• 제49권4호
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• pp.470-476
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• 2017

mTOR 신호전달 단백질의 변화는 다양한 종류의 암에서 관찰 되었다. 따라서 이들 단백질은 최근에 암 치료제에 대한 새롭고 흥미로운 표적이 되고 있다. 우리는 대장암과 선종 환자의 mTOR 세포신호의 활성도를 조사하였다. 면역조직화학적 방법으로 대장암과 선종의 세포신호 단백질 성분인 mTOR, p70-S6K, S6, 4EBP1 발현을 분석하였다. 이번 연구는 모두 100개의 예를 악성(Colorectal Adenocarcinoma, CRAC) 40건, 고등급 선종(Adenoma with High grade intraepithelial neoplasms, HIN) 30건, 저등급 선종(Adenoma with Low-grade intraepithelial neoplasms, LIN) 30건으로 분류하여 진행하였다. p-mTOR의 발현률은 LIN 7%, HIN 30%, CRAC 75%였고 p-S6의 발현률 또한 LIN 10%, HIN 27%, CRAC 55%였다. p-mTOR, p-S6의 발현과 선종-선암 연속성은 중요한 상관관계 있다는 것이 발견되었다. 그리고 흥미롭게도 p-S6 발현률은 진행암보다 초기암에서 더 높았다.

• 생명과학회지
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• 제29권11호
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• pp.1251-1257
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• 2019

본 연구에서는 펩티도글리칸이 단핵세포의 $TNF-{\alpha}$ 발현에 미치는 영향을 조사하였고, 또한 펩티도글리칸에 의한 $TNF-{\alpha}$ 발현에 관련된 세포의 요소들을 연구하였다. 사람의 단핵세포주인 THP-1 세포를 펩티도글리칸에 노출시키는 경우 $TNF-{\alpha}$ 분비 증가뿐만 아니라 $TNF-{\alpha}$ 유전자 전사를 유도하는 결과를 가져왔다. TLR-2/4의 억제제인 OxPAPC은 펩티도글리칸에 의한 $TNF-{\alpha}$의 발현을 저해하였다. 그리고 U0126, SB202190, SP6001250, LY294002, Akti IV, rapamycin, NAC, DPI 같은 약리학적 저해제 또한 $TNF-{\alpha}$ 발현을 유전자/단백질 수준에서 상당히 약화시켰다. 그러나 polymyxin B는 $TNF-{\alpha}$ 발현에 영향을 주지않았다. 따라서 펩티도글리칸이 TLR-2, PI3K, Akt, mTOR, MAPKs, ROS 등을 통하여 단핵세포의 $TNF-{\alpha}$ 발현을 증가시킴을 확인하였다.

• 생명과학회지
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• 제32권6호
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• pp.421-429
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• 2022

본 연구에서는 죽상경화 플락에서 발견되는 펩티도글리칸이 혈관염증에서 어떠한 역할을 하는지 알아보기 위하여 염증성 사이토카인의 한 종류인 인터루킨-1 알파의 발현에 대한 영향을 조사하였다. 실험방법으로는 혈관염증을 주도하는 단핵구/대식세포인 THP-1 세포주에 펩티도글리칸을 처리하고 인터루킨-1 알파의 발현을 RT-PCR, real-time PCR, ELISA 방법으로 분석하였다. 펩티도글리칸의 처리 시간과 농도에 비례하여 단핵구/대식세포에서 인터루킨-1 알파의 전사체와 단백질 분비가 증가함을 관찰하였다. 또한 펩티도글리칸의 작용기전을 규명하기 위하여 신호전달을 차단하는 억제제를 세포에 처리하고 인터루킨-1 알파의 발현을 조사하였다. TLR2/4의 억제제인 OxPAPC 그리고 세포 kinase의 작용을 억제하는 LY294002(PI3 kinase 억제), Akti IV (Akt 억제), rapamycin (mTOR 억제), U0126 (MEK 억제), SB202190 (p38 MAPK 억제), SP6001250 (JNK 억제), DPI (NOX 억제)를 처리하는 경우 인터루킨-1 알파 전사체의 발현 그리고 단백질의 분비가 감소되었다. 반면에 LPS의 작용을 억제하는 polymyxin B는 인터루킨-1 알파의 발현에 영향을 주지 않았다. 이상의 결과는, 펩티도글리칸이 TLR2, PI3K, Akt, mTOR, MAPKs를 통하여 단핵구/대식세포의 인터루킨-1 알파 발현을 증가시키고 혈관염증에 기여한다는 것을 나타낸다.

• BMB Reports
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• 제50권12호
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• pp.601-609
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• 2017

Mammalian target of rapamycin complex 1 (mTORC1) plays a major role in cell growth, proliferation, polarity, differentiation, development, and controls transitioning between anabolic and catabolic states of the cell. It collects almost all extracellular and intracellular signals from growth factors, nutrients, and maintains cellular homeostasis, and is involved in several pathological conditions including, neurodegeneration, Type 2 diabetes (T2D), obesity, and cancer. In this review, we summarize current knowledge of upstream signaling of mTORC1 to explain etiology of T2D and hypertriglyceridemia, in which state, the role of telomere attrition is explained. We discuss if chronic inhibition of mTORC1 can reverse adverse effects resulting from hyperactivation. In conclusion, we suggest the regulatory roles of telomerase (TERT) and hexokinase II (HKII) on mTORC1 as possible remedies to treat hyperactivation. The former inhibits mTORC1 under nutrientrich while the latter under starved condition. We provide an idea of TOS (TOR signaling) motifs that can be used for regulation of mTORC1.

• Asian-Australasian Journal of Animal Sciences
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• 제26권11호
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• pp.1644-1650
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• 2013

Ribosomal protein (rp) S6 is the substrate of ribosomal protein S6K (S6 kinase) and is involved in protein synthesis by mTOR/S6K/S6 signaling pathway. Some S6 cDNA have been cloned in mammals in recent years but has not been identified in the goat. To facilitate such studies, we cloned the cDNA encoding Cashmere goat (Capra hircus) S6 (GenBank accession GU131122) and then detected mRNA expression in seven tissues by real time PCR and protein expression in testis tissue by immunohistochemisty. Sequence analysis indicated that the obtained goat S6 was a 808 bp product, including a 3' untranslated region of 58 bp and an open reading frame of 750 bp which predicted a protein of 249 amino acids. The predicted amino acid sequence was highly homologous to cattle, human, mouse and rat S6. Expression analysis indicated S6 mRNA was expressed extensively in detected tissues and S6 protein was expressed in testis tissue.

• Biomolecules & Therapeutics
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• 제19권3호
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• pp.302-307
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• 2011

Peptidoglycan (PGN) is detected in inflammatory cell-rich regions of human atheromatous plaques. The present study investigated the effects of PGN on CC chemokine ligand 3 (CCL3) expression, which is elevated in the atherosclerotic arteries, and determined cellular factors involved in PGN-mediated CCL3 up-regulation in mononuclear cells, with the goal of understanding the molecular mechanisms of inflammatory responses to bacterial pathogen-associated molecular patterns in diseased arteries. Exposure of human monocytic leukemia THP-1 cells to PGN resulted in enhanced secretion of CCL3 and profound induction of the CCL3 gene transcript. Both events were abrogated by oxidized 1-palmitoyl-2-arachidonosyl-sn-phosphatidylcholine, an inhibitor of Toll-like receptors 2/4. Pharmacological inhibitors such as U0126, SP6001250, Akt inhibitor IV, rapamycin, RO318220, diphenyleneiodonium chloride, and N-acetylcysteine also significantly attenuated PGN-mediated CCL3 up-regulation. However, polymyxin B, LY294002, and SB202190 did not influence CCL3 expression. We propose that PGN contributes to enhanced CCL3 expression in atherosclerotic plaques and that Toll-like receptors (TLR2), Akt, mTOR, mitogen-activated protein kinase, and reactive oxygen species are involved in that process.

• Asian Pacific Journal of Cancer Prevention
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• 제15권16호
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• pp.6463-6475
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• 2014

The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.

• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.127-134
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• 2018

Myofibrillogenesis regulator-1 (MR-1) is a novel protein involved in cellular proliferation, migration, inflammatory reaction and signal transduction. However, little information is available on the relationship between MR-1 expression and the progression of atherosclerosis. Here we report atheroprotective effects of silencing MR-1 in a model of Ang II-accelerated atherosclerosis, characterized by suppression focal adhesion kinase (FAK) and nuclear factor kappaB ($NF-{\kappa}B$) signaling pathway, and atherosclerotic lesion macrophage content. In this model, administration of the siRNA-MR-1 substantially attenuated Ang II-accelerated atherosclerosis with stabilization of atherosclerotic plaques and inhibited FAK, Akt, mammalian target of rapamycin (mTOR) and NF-kB activation, which was associated with suppression of inflammatory factor and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in Ang II-treated vascular smooth muscle cells (VSMCs) and macrophages: siRNA-MR-1 inhibited the expression levels of proinflammatory factor. These studies uncover crucial proinflammatory mechanisms of Ang II and highlight actions of silencing MR-1 to inhibit Ang II signaling, which is atheroprotective.

• Journal of Gastric Cancer
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• 제13권3호
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• pp.129-135
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• 2013

Gastric cancer is the second leading cause of cancer-related deaths worldwide. In advanced and metastatic gastric cancer, the conventional chemotherapy with limited efficacy shows an overall survival period of about 10 months. Patient specific and effective treatments known as personalized cancer therapy is of significant importance. Advances in high-throughput technologies such as microarray and next generation sequencing for genes, protein expression profiles and oncogenic signaling pathways have reinforced the discovery of treatment targets and personalized treatments. However, there are numerous challenges from cancer target discoveries to practical clinical benefits. Although there is a flood of biomarkers and target agents, only a minority of patients are tested and treated accordingly. Numerous molecular target agents have been under investigation for gastric cancer. Currently, targets for gastric cancer include the epidermal growth factor receptor family, mesenchymal-epithelial transition factor axis, and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways. Deeper insights of molecular characteristics for gastric cancer has enabled the molecular classification of gastric cancer, the diagnosis of gastric cancer, the prediction of prognosis, the recognition of gastric cancer driver genes, and the discovery of potential therapeutic targets. Not only have we deeper insights for the molecular diversity of gastric cancer, but we have also prospected both affirmative potentials and hurdles to molecular diagnostics. New paradigm of transdisciplinary team science, which is composed of innovative explorations and clinical investigations of oncologists, geneticists, pathologists, biologists, and bio-informaticians, is mandatory to recognize personalized target therapy.

• 대한의생명과학회지
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• 제15권4호
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• pp.349-353
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• 2009

Lysophosphatidic Acid (LPA) is a bioactive lysophospholipid that is a potent signaling molecule able to provoke a variety of cellular responses in many cell types such as differentiation, inflammation and apoptosis. In this study, we have investigated the effect of LPA on Nitric oxide (NO)-induced apoptosis in rabbit articular chondrocytes. LPA dramatically reduced NO induced apoptosis of chondrocytes determined by phase contrast microscope and MTT assay. When chondrocytes alone treated with LPA, LPA induced phosphorylation of p70S6kinase, a serine/threonine kinase that acts downstream of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphoinositide-dependent kinase-1 (PDK-1) in the PI3 kinase pathway, dose-dependently detected by Western blot analysis. Phosphorylation of p70S6k with LPA was reduced expression of p53 in NO-induced apoptosis of chondrocytes. Also, inhibition of p70S6kinase with rapamycin was enhanced expression of p53 in chondrocytes. Our findings collectively suggest that LPA regulates NO induced apoptosis through p70S6kinase pathway in rabbit articular chondrocytes.