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김광세,Yong-KilHong,YoonLee,Joo-YoungShin,Soo-IkChang,SooIlChung,YoungAeJoe 생화학분자생물학회 2003 Experimental and molecular medicine Vol.35 No.6
The serine protease urokinase-type plasminogen activator (uPA) is im plicated in pericellular proteolysis in a variety of physiological and pathological processes including angiogenesis and tumor metastasis. The kringle domain of uPA (UK1) has proven to be an anti-angiogenic molecule with unknown mechanism and amino terminal fragment of uPA (u-ATF) with additional growth factor-like domain can be used for blocking interaction of uPA and uPA receptor. Here, we compared anti-angiogenic activities of these two molecules in vitro and in vivo. The recombinant u-ATF from E. coli and refolded in vitro was found to bind to uPAR with high affinity, whereas E. coli-derived UK1 showed no binding by Biacore analysis. In contrast to UK1 having potent inhibitory effect, u-ATF exhibited low inhibitory effect on bovine capillary endothelial cell growth (ED50>320 nM). Furthermore, u-ATF inhibition of VEGF-induced migration of human umbilical vein endothelial cell was far less sensitive (IC50 = 600 nM) than those observed with UK1, and angiogenesis inhibition was marginal in chorioallantoic membrane. These results suggest that kringle domain alone is sufficient for potent antiangiogenic activity and additional growth factor-like domain diverts this molecule in undergoing different mechanism such as inhibition of uPA/uPAR interaction rather than undergoing distinct antiangiogenic mechanism driven by kringle domain.
Antiangiogenic and Antitumor Activities of the Cryptic Fragments with Kringle Architecture
( Young Ae Joe ),( Myung Rae Kim ),( Byoung Shik Shim ),( Dae Shik Oh ),( Sung Hee Hong ),( Yong Kil Hong ) 한국응용약물학회 2003 Biomolecules & Therapeutics(구 응용약물학회지) Vol.11 No.4
N/A Various angiogenesis inhibitors target vascular endothelid cells and block tumor angiogenesis. Angiostartin is a specific endogenous angiogenesis inhibitor in clinical trials, which contains only the first four triple loop structures, known as kringle domains. Its generated by proteolytic cleavage of its parent molecule plasminogen, which itself does not exhibit anti-angiogenic activity. Kringle domains from prothrombin, apolipoprotein, hepatocyte growth factor, urokinase and tissue-type plasminogen activator also elicit anti-angiogenic or antitumor activities in several model systems, albeit low amino acid sequence identity between angiostatin and each individual kringle. However, the differential effects of each kringle domain on endothelial cell proliferation, and migration observed in these kringle domains, suggest that the amino acid sequence of the primary structure is still important although kringle architecture is essential for anti-angiogenic activity. If it is further studied as to how amino acid sequence and kringle architecture contributes in anti-angiogenic activity, with studies on underlying mechanisms of anti-angiogenesis by kringle-based angiogenesis inhibitors, it will provide basis for the development of new potent anti-angiogenesis inhibitors and improvement of the efficacy of angiogenesis inhibitors.
( Young Ae Joe ),( Hyun Sun Lee ),( Eun Ju O ),( Kwang Sei Kim ) 한국응용약물학회 2010 Biomolecules & Therapeutics(구 응용약물학회지) Vol.18 No.4
Bone marrow-derived mesenchymal stem cells (BM-MSC) are a multipotent cell population that can differentiate into neuron-like cells. Previously it has been reported that murine BM-MSC can differentiate into neuron-like cells by co-treatment with a Rho-associated kinase (ROCK) inhibitor -Y27632 and CoCl2. In this study, we compared several ROCK inhibitors for the ability to induce human BM-MSCs to differentiate into neuron-like cells in the presence of CoCl2. Y27632 with high specificity for ROCK at 1-30 μM was best at inducing neuronal differentiation of MSCs. Compared to HA1077 and H1152, which also effectively induced morphological change into neuron-like cells, Y27632 showed less toxicity even at 100 μM, and resulted in longer multiple branching processes at a wide range of concentrations at 6 h and 72 h post-induction. H89, however, which has less specificity by inhibition of protein kinase A, S6 kinase 1 and MSK1 with similar or greater potency, was less effective at inducing neuronal differentiation of MSCs. Simvastatin, which can inhibit Rho, Ras, and Rac by blocking the synthesis of isoprenoid intermediates, showed little activity for inducing morphological changes of MSCs into neuron-like cells. Accordingly, the expression patterns for neuronal cell markers,including β-tubulin III, neuron-specific enolase, neurofilament, and microtubule-associated protein, were consistent with the pattern of the morphological changes. The data suggest that the ROCK inhibitors with higher specificity are more effective at inducing neuronal differentiation of MSCs.