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Cha, Hee-Jae,Bae, Soo-Kyung,Lee, Ho-Young,Lee, Ok-Hee,Sato, Hiroshi,Seiki, Motoharu,Park, Byung Chae,Kim, Kyu-Won 부산대학교 유전공학연구소 1996 분자생물학 연구보 Vol.12 No.-
We examined the anti-invasive activity of ursolic acid (UA) on the highly metastatic HT1080 human fibrosarcoma cell line. UA reduced tumor cell invasion through a reconstituted basement membrane in a transwell chamber. A significant down-regulation of matrix metalloproteinase-9[MMP-9; M_r 92,000 gelatinase/type IV collagenase (collagenase B)] by UA was detected by Northern blot analysis. However, MMP-2[M_r 72,000 gelatinase/type IV collagenase (collagenase A)]and membrane-type MMP were constantly expressed, and the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 also was not changed after 3 and 6 days of treatment with UA. Quantitative gelatin-based zymography confirmed a markedly reduced expression of MMP-9 but not MMP-2 after treatment with UA. To confirm the UA-induced down-regulation of MMP-9 expression, we constructed a secreted alkaline phosphatase (SEAP) reporter vector into HT1080 cells, reduced SEAP activity was detected after treatment with UA. These results suggest that down-regulation of MMP-9 contributes to the anti-invasive activity of UA in HT1080 cells.
Cha, Hee-Jae,Park, Moon-Taek,Chung, Hae-Young,Kim, Nam-Deuk,Sato, Hiroshi,Seiki, Motoharu,Kim, Kyu-Won 부산대학교 유전공학연구소 1998 분자생물학 연구보 Vol.14 No.-
We have previously reported that ursolic acid, a pentacyclic triterpene acid, inhibited the invasion of HTI1080 human fibrosacrcoma cells by reducing the expression of matrix metalloproteinase-9. Since the chemical structure of ursolic acid is very similar to that of dexamethasone, a synthetic glucocorticoid, we investigated whether ursolic acid acts through the glucocorticoid receptor. The expression of matrix metalloproteinase-9 is thought to be regulated similary with matrix metalloproteinase-1 and matrix metalloproteinase-3 as containing common 2-0-teradecanoylphorbol-acetate responsible region, where AP-1 proteins can bind. Dexamethasone has been studied to respress the 2-0-teradecanoylphorbol-acetate-induced expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 through a glucocorticoid receptor-mediated manner. In Northern biot analysis, we found that ursolic acid reduced the expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 induced by 2-0-teradecanoylphorbol-acetate. Similarly, ursolic acid down-regulated 2-0-teradecanoylphorbol-acetate-induction of matrix metalloproteinase-9 gene in the same manner of dexamethasone. RU486, a potent glucocorticoid receptor antagonist, was used for identifying that ursolic acid-induced down-regulation of matrix metalloproteinase-9 expression is mediated by its binding to glucocorticoid receptor. The effect of ursolic acid on the matrix metalloproteinase-9 expression was blocked by RU486, suggesting that ursolic acid acts via a glucocorticoid receptor in the regulation of matrix metalloproteinase-9. Western blot analysis and immunocytochemistry showed that urslic acid increased glucocorticoid receptor fraction in the muscleus, although it decreased the synthesis of glucocorticoid receptor mRNA. In addition, ursolic acid did not decrease the expression of c-jun and DNA-binding activity of AP-1 to its cognate sequences. Taken together, we suggest that ursolic acid may induce the repression of matrix metalloproteinase-9 by stimulating the muclear translocation of glucocorticoid receptor, and the translocated glucocorticoid receptor probably down-modulating the trans-activating function of AP-1 to 2-0-teradecanoylphorbol-acetate responsible element of matrix metalloproteinase-9 promoter region.