Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines

Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFα is an apoptotic inducer in some cancer cells, it activates NFκB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFκB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFα, thus converting TNFα from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTα, FasL, and TRAIL. Mechanistically, CCNs function through integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding α6β1-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an α6β1-HSPG-binding defective CCN1 are blunted in TNFα- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFα and related cytokines

TNFα-Induced Apoptosis Enabled by CCN1/CYR61: Pathways of Reactive Oxygen Species Generation and Cytochrome c Release

Although TNFα is a strong inducer of apoptosis, its cytotoxicity in most normal cells in vitro requires blockade of NFκB signaling or inhibition of de novo protein synthesis, typically by the addition of cycloheximide. However, several members of CCN (CYR61/CTGF/NOV) family of extracellular matrix proteins enable TNFα-dependent apoptosis in vitro without inhibiting NFκB or de novo protein synthesis, and CCN1 (CYR61) is essential for optimal TNFα cytotoxicity in vivo. Previous studies showed that CCN1 unmasks the cytotoxicity of TNFα by binding integrins αvβ5, α6β1, and the cell surface heparan sulfate proteoglycan syndecan 4 to induce the accumulation of a high level of reactive oxygen species (ROS), leading to a biphasic activation of JNK necessary for apoptosis. Here we show for the first time that CCN1 interacts with the low density lipoprotein receptor-related protein 1 (LRP1) in a protein complex, and that binding to LRP1 is critical for CCN1-induced ROS generation and apoptotic synergism with TNFα. We also found that neutral sphingomyelinase 1 (nSMase1), which contributes to CCN1-induced ROS generation, is required for CCN1/TNFα-induced apoptosis. Furthermore, CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFα. By contrast, LRP1, nSMase1, p53, and p38 MAPK are not required when TNFα-dependent apoptosis is facilitated by the presence of cycloheximide, indicating that they function in the CCN1 signaling pathway that converges with TNFα-induced signaling events. Since CCN1/CYR61 is a physiological regulator of TNFα cytotoxicity at least in some contexts, these findings may reveal important mediators of TNFα-induced apoptosis in vivo and identify potential therapeutic targets for thwarting TNFα-dependent tissue damage

Function of Cyr61 and CTGF in cell adhesive signaling, gene expression, wound healing and breast cancer.

Function of Cyr61 and CTGF in cell adhesive signaling, gene expression, wound healing and breast cancer

Study on the Construction of the Ubiquitous Computing Environment-on Digital Chicken Farm

普及運算讓使用者將注意力由設備的操作轉移到所提供的應用服務上，讓人機之間的互動能夠更有效率以及有更自然的操作性，並且普及運算的發展使得資訊技術融入到日常生活中的每個角落，讓使用者隨時隨地、無時無刻都能享受資訊技術所提供的服務。 數位養雞場為整合了實體農場與虛擬農場入口網的一項服務，建立出符合普及運算概念的環境，旨在利用資訊技術讓使用者認養寵物，將寵物飼養在農場裡，並透過網路上的虛擬農場看到寵物的生活而且能遠端飼養寵物，因此在工作壓力沉重的平日亦能輕鬆享受飼養寵物的愉悅；當例假日時使用者可攜同全家大小，至實體農場跟寵物進行實際的互動，享受愜意的休閒生活。使用者飼養過程中所需要的知識，將建置成一個完整的數位學習網讓使用者學習，以達到寓教於樂的功能。數位養雞場內所有雞隻以RFID技術為基礎建立產銷履歷制度，讓農產品的來源與健康能獲得品質保證。本論文旨在提出數位養雞場的概念及對其普及運算的運作模式做出探討，並實作出一個數位養雞場入口網站的雛型，同時也希望農場業者能應用這一項服務，讓終日繁忙的社會大眾雖身處於都市叢林、但也可以便利地享有健康的休閒生活，為傳統休閒農業市場開創出一片新的藍海。Ubiquitous computing is emerging as a concept with transforming the attention of users from the operation of devices into the application of services. It changes current human computer interaction model. The development of ubiquitous computing allows that the capacity of computing can be diffused to everyone's life and then it provides services of the computing everywhere at any time. Digital Chicken Farm is a service which integrates the physical farm and the virtual Web portal to construct an ubiquitous computing environment. Users can foster pets and raise them up in the farm. They can watch their pets through the virtual Web interface, and hence users can enjoy the happiness of raising up pets though they are at home or office. Users can go to the physical farm and play with the pets in weekend or on holidays, so they can have a really cheerful leisure time and relax their pressure. An e-learning website is constructed to offer the users knowledge needed when raising up pets, users not only play with the pets in virtual world but they can learn knowledge with our service. Therefore the digital chicken farm would infuse entertainment into user's learning. We plan to apply traceability system on every single live using RFID technology in the digital chicken farm and hence promise the quality of source and health of the lives. The aims of the proposed work are to study the operational model and architecture of the digital chicken farm on the ubiquitous computing environment and to construct a prototype of the Web portal for the digital chicken farm. Accordingly, we hope the farm vendors can apply the proposed model to construct an applicable and profitable marketing strategy.摘要............................................I Abstract.......................................II 目次..........................................III 表目次..........................................V 圖目次.........................................VI 第一章 緒論.....................................1 第一節 研究背景.................................1 第二節 研究動機與目的...........................2 第三節 研究方法與架構...........................4 第二章 文獻探討.................................6 第一節 普及運算(Ubiquitous Computing)...........6 第二節 數位學習.................................7 第三節 無線射頻識別(RFID)......................10 第四節 產銷履歷系統(Traceability system).......17 第五節 小結....................................22 第三章 數位養雞場之分析與規劃..................23 第一節 環境建置................................25 第二節 運作模式................................32 第三節 結合數位學習之規劃......................39 第四節 產銷履歷制度之規劃......................45 第四章 網站實作................................50 第一節 網站規劃................................50 第二節 網站實作與展示..........................59 第五章 結論與建議..............................69 第一節 結論....................................69 第二節 未來建議................................71 參考書目.......................................7

Functions and mechanisms of action of CCN matricellular proteins

a b s t r a c t Members of the CCN (CYR61/CTGF/NOV) family have emerged as dynamically expressed, extracellular matrix-associated proteins that play critical roles in cardiovascular and skeletal development, injury repair, fibrotic diseases and cancer. The synthesis of CCN proteins is highly inducible by serum growth factors, cytokines, and environmental stresses such as hypoxia, UV exposure, and mechanical stretch. Consisting of six secreted proteins in vertebrate species, CCNs are typically comprised of four conserved cysteine-rich modular domains. They function primarily through direct binding to specific integrin receptors and heparan sulfate proteoglycans, thereby triggering signal transduction events that culminate in the regulation of cell adhesion, migration, proliferation, gene expression, differentiation, and survival. CCN proteins can also modulate the activities of several growth factors and cytokines, including TGF-␤, TNF␣, VEGF, BMPs, and Wnt proteins, and may thereby regulate a broad array of biological processes. Recent studies have uncovered novel CCN activities unexpected for matricellular proteins, including their ability to induce apoptosis as cell adhesion substrates, to dictate the cytotoxicity of inflammatory cytokines such as TNF␣, and to promote hematopoietic stem cell self-renewal. As potent regulators of angiogenesis and chondrogenesis, CCNs are essential for successful cardiovascular and skeletal development during embryogenesis. In the adult, the expression of CCN proteins is associated with injury repair and inflammation, and has been proposed as diagnostic or prognostic markers for diabetic nephropathy, hepatic fibrosis, systemic sclerosis, and several types of cancer. Targeting CCN signaling pathways may hold promise as a strategy of rational therapeutic design

TNFa-Induced Apoptosis Enabled by CCN1/CYR61: Pathways of Reactive Oxygen Species Generation and Cytochrome c Release

Although TNFa is a strong inducer of apoptosis, its cytotoxicity in most normal cells in vitro requires blockade of NFkB signaling or inhibition of de novo protein synthesis, typically by the addition of cycloheximide. However, several members of CCN (CYR61/CTGF/NOV) family of extracellular matrix proteins enable TNFa-dependent apoptosis in vitro without inhibiting NFkB orde novo protein synthesis, and CCN1 (CYR61) is essential for optimal TNFa cytotoxicity in vivo. Previous studies showed that CCN1 unmasks the cytotoxicity of TNFa by binding integrins a vb 5, a 6b 1, and the cell surface heparan sulfate proteoglycan syndecan 4 to induce the accumulation of a high level of reactive oxygen species (ROS), leading to a biphasic activation of JNK necessary for apoptosis. Here we show for the first time that CCN1 interacts with the low density lipoprotein receptor-related protein 1 (LRP1) in a protein complex, and that binding to LRP1 is critical for CCN1-induced ROS generation and apoptotic synergism with TNFa. We also found that neutral sphingomyelinase 1 (nSMase1), which contributes to CCN1-induced ROS generation, is required for CCN1/TNFa-induced apoptosis. Furthermore, CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFa. By contrast, LRP1, nSMase1, p53, and p38 MAPK are not required when TNFa-dependent apoptosis is facilitated by the presence of cycloheximide, indicating that they function in the CCN1 signaling pathway that converges with TNFa-induced signaling events. Since CCN1/CYR61 is a physiological regulator of TNFa cytotoxicity at least in some contexts, thes