Thrombospondin-1과 종양형성 억제작용

정구보(Goo-Bo Jeong) 대한체질인류학회 2015 대한체질인류학회지 Vol.28 No.4

Thrombospondin-1 (TSP-1)은 여러 가지 세포 수용체를 통해 혈관내피세포 및 암세포의 활성을 조절할 수 있는 다양한 기능을 갖는 단백질로 신혈관형성을 억제하며, 혈관내피세포와 암세포의 부착, 세포증식, 이동 및 세포의 생존 등을 조절한다. 또한 여러 연구자들에 의해 TSP-1의 발현을 증가시키면 종양의 성장과 전이가 억제되고 신혈관형성이 차단됨이 확인되었다. 신혈관형성 억제제는 지난 30년간 VEGF (vascular endothelial growth factor)의 신호전달기전을 차단하는 억제제를 중심으로 개발되어 왔으며 tyrosine kinase의 저분자 억제제들이 치료제로 승인되었다. TSP-1은 여러 가지 기능성 도메인을 갖고 있어서 CD36과 CD47 수용체를 통해 종양의 신혈관형성을 억제한다. TSP-1은 CD47과의 결합을 통해 VEGFR2의 인산화를 억제하고 하위신호전달 물질인 AKT 활성화를 차단하여 혈관내피세포에 대한 VEGF의 작용을 억제한다. 최근 CD47 수용체에 결합하는 단클론항체를 이용하여 CD47 수용체의 작용을 차단하면 큰포식세포와 세포독성 T 림프구의 작용을 활성화하여 암세포를 제거할 수 있다는 사실이 밝혀졌다. 이러한 사실들은 TSP-1에 의해 암세포를 제거하고 종양의 혈관형성을 억제할 수 있는 새로운 시대가 도래하고 있음을 시사하는 것이다. Thrmobospondin-1 is the multifunctional protein that modulates endothelial cell and tumor cell behavior via several cell surface receptors and inhibits angiogenesis. In vitro, thrombospondin-1 alters adhesion, proliferation, motility, and survival of endothelial and cancer cells. Studies have confirmed that increased TSP-1 expression suppresses growth or metastasis of some tumors and inhibits angiogenesis. In the past three decades, inhibitors of angiogenesis have been developed as regulators target the vascular endothelial growth factor (VEGF) signaling pathway and small molecule tyrosine kinase inhibitors have been clinically approved. TSP-1 has several functional domain structures and inhibits tumor angiogenesis by engaging receptors CD36 and CD47. TSP-1 binding to CD47 dissociates it from VEGFR2, inhibiting downstream AKT activation and functional responses of endothelial cells to VEGF. Recently, macrophage phagocytosis and cytotoxic T-cell induction of tumor cells mediated by CD47-specific blocking antibodies have been proposed. These findings provide a new therapeutic paradigm for elinination of cancer cells and inhibition of angiogenesis of tumor by TSP-1.

Roles of Tsp66E and Tsp74F in border cell migration and the maintenance of border cell adhesion in Drosophila

정해민,한승엽,이민정,이수진,신명철,전영재,이경호,조경상 한국유전학회 2015 Genes & Genomics Vol.37 No.6

KAI1/CD82, a member of the tetraspanin superfamily, is a tumor metastasis suppressor implicated in cell migration and adhesion in various tumor cells. Drosophila expresses an orthologue of KAI1/CD82, Tsp66E. However, the role of Tsp66E in cell migration and adhesion has not been studied. Here, we investigated the roles of Tsp66E in border cell migration and border cell adhesion, which are well-established in vivo models of cell migration and adhesion. Border cell migration was accelerated by loss of Tsp66E but delayed by Tsp66E overexpression. Deficiency of Tsp74F, a Drosophila orthologue of human Tspan11 and CD151, further increased the migration rate of Tsp66E mutant border cells. In addition, the premature detachment of border cells at stage 8 oogenesis induced by the loss of inflated, which encodes aPS2 integrin, was enhanced by Tsp66E deficiency. Interestingly, Tsp74F deficiency further enhanced the phenotype. aPS2 and bPS integrins were highly expressed in anterior follicle cells before border cell migration, consistent with an important role in border cell adhesion. The results suggest that Tsp66E and Tsp74F cooperate to negatively regulate border cell migration, support the integrin-mediated maintenance of border cell adhesion, and prevent premature migration.

Helixor A는 시험관 내에서 thrombospondin-1의 상승조절을 통해 신혈관생성을 억제한다.

염동훈,홍경자,Yeom Dong-Hoon,Hong Kyong-Ja Korean Society of Life Science 2005 생명과학회지 Vol.15 No.6

Thrombospondin-1은 암성장과 신혈관생성 억제조절인자로 병리학적 조건과 세포외에서의 자극에 의해 세포 특이적으로 조절되어지고 이 TSP-1 유전자 발현조절은 암치료제 개발을 위한 새로운 접근으로 중요하다. Mistletoe는 기생식물로 면역조절과 항암제로 사용되어지고 있다. Helixor A는 mistletoe 추출물의 수용액부분이다. 여기서 우리는 Helixor A를 투여하면 간암세포주 (Hep3B)와 혈관내피세포주 (BAE)에서 TSP-1의 mRWA와 단백질 발현이 유도되는 것을 관찰하였다. TSP-1 promoter 활성분석으로 TSP-1유전자의 발현이 Helixor A에 의해 전사단계에서 조절되어 진다는 것을 확인하였다. 세포 침윤 분석에서 Helixor A를 처리한 배지를 두 세포주에 처리함으로 침윤된 세포의 수가 현저하게 줄어드는 것을 관찰하였고, Matrigel에서 혈관 내피 세포 (BAE)의 모세관 형성을 억제하는 것을 관찰하였다. 또한 세포 침윤과 모세관 형성에서 Helixor A를 처리했던 배지의 억제 효과가 TSP-1 중화 항체에 의해 그 효과가 상실되었다. 그러므로, 이 결과는 TSP-1이 Helixor A에 의해 유도되어진 혈관신생 억제 효과에 연관이 있음을 제시하였다. 이러한 결과를 종합 하였을 때 Helixor A가 TSP-1의 상승조절을 통해 혈관신생 억제 효과를 가질 것이라고 생각된다. Thrombospondin-1 (TSP-1), a negative regulator in tumor growth and angiogenesis, is cell-type specifically regulated under pathological conditions or by extracellular stimuli, and the regulation of TSP-1 gene expression is important for developing new approaches in tumor therapy. Mistletoe is a parasitir plant that have been used for immunomodulation and antitumor therapy. Helixor A is an aqueous part of mistletoes extract. Here we showed that TSP-1 expression was significantly induced at both mRNA and protein levels in the Hepatocarcinorna cell line (Hep3B) and primary bovine endothelial cell line (BAE) exposed to Helixor A. Our promoter analysis confirmed that the expression of TSP-1 gene was regulated by Helixor A at the transcriptional level. In cell invasion assay, the conditioned media obtained from treatment of these cells significantly reduced the number of invasive cells and also inhibited capillary-like tube formation of BAE cells on Matrigel. Moreover, the inhibitory efforts of the conditioned media on cell invasion and tube formation were reversed by blocking with anti-TSP-1 neutralizing antibodies, suggesting that TSP-1 is involved in Helixor A-indured antiangiogenic effect. Taken together, our results suggest that Helixor A have an antiangiogenic effects through upregulation of TSP-1.

The Modulation of Cell Wall-Associated Triton X-100 Soluble Protein (TSP) Antigens of Mycobacterium tuberculosis on Murine Dendritic Cells

Yung-Choon Yoo,Young-Joo Bae,Tae-Hyun Paik,Junglim Lee 한국실험동물학회 2008 Laboratory Animal Research Vol.24 No.4

Mycobacterium tuberculosis or its secreted protein antigens are known as a potent inducer of maturation process of dendritic cells, during which the expression of cell surface molecules and the capability of antigen presentation are increased, resulting in potent interaction with T cells to initiate the acquired immune response against tuberculosis. In this study, the cell wall-associated Triton X-100 soluble protein (TSP) antigens, TSP- BCG, TSP-H37Ra, TSP- H37Rv and TSP-K, were tested on murine bone marrowderived dendritic cells to determine the capability of their immunologic modulation. Only TSP-H37Rv stimulated murine dendritic cells showed moderate production of IL-6 and MIP-1α compared to those of LPS. TSP-H37Rv antigen did not induce the production of IL-12, TNF-α or IL-10. Other TSP antigenstimulated murine dendritic cells showed minimal or no induction of cytokines (IL-6, IL-12, TNF-α or IL-10) or chemokines (MIP-1α or RANTES). The murine dendritic cells showed the production of NO as well as the expression of iNOS mRNA after LPS stimulation, however, none of TSP antigen-stimulated murine dendritic cells induced either NO or iNOS mRNA expression. The allostimulation of T cells by murine dendritic cells, which were stimulated with each TSP antigens, showed insignificant increase in T cell proliferation activity in mixed lymphocyte reaction. These results suggested that cell wall-associated TSP antigen isolated from Mycobacterium tuberculosis H37Rv strain acts as a more potent stimulator on murine dendritic cells than any other TSP antigens, even the stimulation from TSP-H37Rv was not enough to activate the maturation of process of murine dendritic cells.

Thrombospondin-2 Couples Pressure-Promoted Chondrogenesis through NF-κB Signaling

Niu Jing,Feng Fan,Zhang Songbai,Zhu Yue,Song Runfang,Li Junrong,Zhao Liang,Wang Hui,Zhao Ying,Zhang Min 한국조직공학과 재생의학회 2023 조직공학과 재생의학 Vol.20 No.5

BACKGROUND: Our previous studies found that the mechanical stimulation promote chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), along with up-regulation of thrombospondin-2 (TSP-2). The aim of this study was to explore the effect of thrombospondin-2 (TSP-2) on the mechanical pressure-stimulated chondrogenic differentiation of BMSCs and the possible role of NF-jB signaling in the mechano-chemical coupling regulation toward chondrogenesis. METHODS: Rat BMSCs were isolated, cultured and identified. The time-dependent expressions of TSP-2 and Sox9 in BMSCs under a dynamic mechanical pressure of 0–120 kPa at 0.1 Hz for 1 h were tested by qPCR and Western blotting. The role of TSP-2 in chondrogenic differentiation of BMSCs under mechanical pressure was validated by using small interfering RNA. The impact of TSP-2 and mechanical pressure on chondrogenesis were detected and the downstream signaling molecules were explored using Western blotting. RESULTS: Mechanical pressure stimulation of 0–120 kPa for 1 h significantly upregulated the expression of TSP-2 in BMSCs. The expression of the chondrogenesis markers Sox9, Aggrecan, and Col-II were all upregulated under dynamic mechanical pressure or TSP-2 stimulation. Additional exogenous TSP-2 may potentiate the chondrogenic effect of mechanical stimulation. After knock down TSP-2, the upregulation of Sox9, Aggrecan and Col-II under mechanical pressure was inhibited. The NF-jB signaling pathway responded to both dynamic pressure and TSP-2 stimulation, and the cartilage-promoting effect was blocked by an NF-jB signaling inhibitor. CONCLUSION: TSP-2 plays an essential role in the chondrogenic differentiation of BMSCs under mechanical pressure. NF-jB signaling is involved in the mechano-chemical coupling of TSP-2 andmechanical pressure for the chondrogenic differentiation of BMSCs.

버스 통행우선신호 도입에 관한 연구

김성득 한국항해항만학회 2005 한국항해항만학회지 Vol.29 No.5

버스 통행우선신호(TSP)와 관련된 외국의 사례를 살펴본 결과 버스운행시간이 6~32% 감소하였다. TSP 기법을 울산도심의 주간선도로인 문수로 4.07㎞ 구간에 오전 첨두시 1시간의 동진하는 버스에 대해서 Early Green과 Extended Green기법을 적용하였다. 앞의 기법에서 평균 통행시간이 18.1~25.8% 단축되었고 통행속도는 30.9~40.1% 빨라졌다. 뒤 기법에서는 통행시간이 12.1~30.3% 단축되었고, 통행속도는 30.1% 빨라졌다. 따라서 우리나라에서도 버스 TSP를 도입할 수 있을 것이다 In the analysis of the foreign cases on the use of Transit Signal Priority(TSP), the reduction in bus travel time ranged from 6 to 32%. This study demonstrates how TSP can be applied to Ulsan Metropolitan City. TSP techniques were used on the bus routes that run eastward for 4.07 kilometers along Munsoo-Ro, a major artery in the most congested part of the city. The simulation was performed on one hour of peak traffic time, using the two TSP strategies of Early Green and Extended Green. The use of the Early Green strategy resulted in an average decrease in travel time ranging from 18.1 to 25.8 % and an increase in average travel speed ranging from 30.9 to 40.1 %. The Extended Green strategy resulted in an average decrease in travel time ranging from 18.1 to 30.3 % and an increase in an average travel speed of approximately 30.1 %. This study demonstrates that TSP is effective in decreasing travel time and increasing travel speed of the bus system in Korea.

Identification of a Cys-motif Gene, TSP13, as a Putative Host Translation Inhibitory Factor in Plutella xylostella-Cotesia plutellae

Eunseong Kim,Yeongtae Kim,Yonggyun Kim 한국응용곤충학회 2015 한국응용곤충학회 학술대회논문집 Vol.2015 No.04

Translational control is a strategy for various viruses to manipulate their hosts to suppress any acute antiviral activity. Some cys-motif genes encoded in polydnaviruses or teratocytes act as host translation inhibitory factor (HTIF) to defend the host antiviral activity. A novel cys-motif gene, TSP13, was encoded in the genome of an endoparasitoid wasp, Cotesia plutellae. TSP13 consists of 129 amino acid residues with a predicted molecular weight of 13.987 kDa and pI value at 7.928. Genomic DNA region encoding open reading frame is interrupted with three introns. TSP13 was expressed in Plutella xylostella larvae parasitized by C. plutellae. C. plutellae bracovirus (CpBV) was purified and injected to nonparasitized P. xylostella. In the virus-injected P. xylostella, TSP13 was shown to be expressed by RT-PCR analysis. Thus, TSP13 was turned out to be encoded in the proviral CpBV genome. TSP13 was cloned into a eukaryotic expression vector, which was then used to infect Sf9 cells to transiently express TSP13. The synthesized TSP13 was detected in the culture broth. Purified TSP13 significantly inhibited cellular immune responses. Furthermore, TSP13 entered the target cells and was localized in the cytosol. This study reports a novel cys-motif gene, which is encoded in CpBV genome localized on chromosome(s) of C. plutellae and replicated to be encapsidated in the episomal viral particles during parasitization.

자기정전용량 방식의 TSP에서 멀티터치 인식 및 추적

정성훈(Sung Hoon Jung) 한국지능시스템학회 2014 한국지능시스템학회논문지 Vol.24 No.2

본 논문에서 우리는 자기정전용량 방식의 TSP(Touch Screen Pannel)에서 멀티터치를 인식하고 추적하는 방법에 대하여 소개한다. 자기정전용량 방식의 TSP는 패널의 가로와 세로로 배치된 ITO 투명전극필름 자체의 정정용량변화를 센싱하여 터치를 인식하는 방법으로 SNR이 좋고 센싱시간이 빠르며 터치인식 및 처리가 간단한 장점이 있으나 멀티터치 처리에 어려운 단점이 있다. 이러한 이유로 최근에는 멀티터치에 어려움이 없는 상호정전용량 방식의 TSP가 많이 사용되고 있다. 그러나 소형으로 개발되는 리모컨 패드나 최근에 개발되고 있는 착용기기에서는 제한된 멀티터치만으로 가능하므로 큰 문제가 되지 않는다. 본 논문에서는 이러한 자기정전용량 방식의 TSP에서 멀티터치를 인식할 때 발생하는 문제와 이러한 문제를 완화하는 방법 그리고 터치이동 시에 이를 추적하는 방법에 대하여 제안한다. 제안한 방법을 실험한 결과 투 터치에서 안정적으로 동작함을 확인하였다. This paper introduces a multi-touch recognition and tracking method for self capacitive TSP(Touch Screen Pannel). Self capacitive TSP recognizes finger touches by sensing capacitive change of ITO transparent conducting film arranged by rows and columns on the TSP pannel. They have some advantages such as high SNR, fast sensing, and simple touch processing, but have very difficulties for multi-touch processing. This disadvantage makes that the mutual capacitive TSPs, which have no such disadvantage, have been more widely used especially for multi-touch applications. However, since the other applications for remote control pad or recently developed wearable devises have only restrictive requirements for multi-touch, the disadvantage of self capacitive TSP is not a critical problem. In this paper, we first describe multi-touch recognition problems in self capacitive TSP and then propose how to overcome those problems and a tracking method of two touches when they are moving. Experimental results of our method showed that our algorithm works well in two touches.

센서네트워크 상의 TSP 경로구성 방법에 대한 분석

김준모(Joonmo Kim) 大韓電子工學會 2010 電子工學會論文誌-TC (Telecommunications) Vol.47 No.11

센서네트워크 등에서 단말 또는 노드들을 한 번씩 모두 방문하는 최적의 라우팅 경로를 동적으로 찾는 문제가 대두된다. 이러한 문제를 근사하게 해결 할 수 있는 일반화된 scheme을 제시하고, 이를 기반으로 구성되는 알고리즘의 실행시간 및 그 결과의 바운드를 수리적으로 정립하면, 주어진 네트워크에서 구축되는 라우팅 경로를 수리적으로 분석 할 수 있게 된다. 본 논문은 이러한 문제를 대표하는 Euclidean TSP(Euclidean Travelling Sales Person) 문제를 대상으로 하여, 근사 Euclidean TSP를 병렬처리 형태로 구성할 수 있는 scheme을 제공하고, 이 scheme에 의해 구해 질 수 있는 근사 Euclidean TSP가 최적의 Euclidean TSP와 어느 정도의 차이를 가지게 되는지 판단할 수 있는 기준을 제시한다. In Sensor Networks, the problem of finding the optimal routing path dynamically, which passes through all terminals or nodes once per each, may come up. Providing a generalized scheme of approximations that can be applied to the kind of problems, and formulating the bounds of the run time and the results of the algorithm made from the scheme, one may evaluate mathematically the routing path formed in a given network. This paper, dealing with Euclidean TSP(Euclidean Travelling Sales Person) that represents such problems, provides the scheme for constructing the approximated Euclidean TSP by parallel computing, and the ground for determining the difference between the approximated Euclidean TSP produced from the scheme and the optimal Euclidean TSP.

핵자기공명분광법에 사용되는 D2O 및 TSP의 세포 독성 평가

문치웅 ( Chi Woong Mun ),곽소영 ( So Young Kwak ),장무영 ( Moo Young Jang ) 한국조직공학·재생의학회 2012 조직공학과 재생의학 Vol.9 No.2s

Nuclear magnetic resonance (NMR) spectroscopy has been being used to identify cell metabolite and differentiation with reference material (TSP) and locking solvent (D2O). The aim of this study is to evaluate the cytotoxicity of TSP and D2O which have been widely used for NMR research. MG-63 and hMSC were selected and cultured in 3-dimensions on alginate bead for cytotoxicity test. The statistical analysis was performed after identifying the cell viability in accordance with various concentrations and exposure time of TSP and D2O. There was significant difference of cell viability between two concentrations (40% and 100%) of locking solvent (D2O). Our results indicate that the increased concentration of D2O effects the reduction of cell viability on two different cell types (MG-63: 4%, hMSC:14~40%). However, there was no significant difference by concentration of TSP. The statistical significance and cytotoxicity of concentration were found on D2O but not on TSP except for exposed hMSC for 24 hours from TSP. No statistical significance was found according to exposure time of D2O and TSP. We concluded that TSP still can be used for NMR but the use of D2O should be prohibited when identifying cell metabolite and differentiation. So, another locking solvent except D2O is needed.