Hosono T, Ito A, Sato T, Nagase H, Mori Y
Department of Biochemistry, Tokyo College of Pharmacy, Japan.
Biol Pharm Bull. 1996 Oct;19(10):1285-90. doi: 10.1248/bpb.19.1285.
We have previously reported that epidermal growth factor (EGF) augments the translation of pro-matrix metalloproteinase 3 (proMMP-3/prostromelysin 1) and tissue inhibitor of metalloproteinases (TIMP)-1 mRNAs during the first 1-h treatment of human uterine cervical fibroblasts (Hosono, T. et al., FEBS Lett., 381, 115-118, (1996)). In this report, we have investigated the effect of interleukin 1 alpha (IL-1 alpha) and 12-O-tetradecanoylphorbol 13-acetate (TPA), potent stimulators of proMMPs and TIMP-1 production, on the translation of proMMP-3 and TIMP-1 mRNAs. When human uterine cervical fibroblasts were treated with IL-1 alpha or TPA for 2h, their translations were not augmented, whereas the steady-state levels of proMMP-3 and TIMP-1 mRNAs in the cells treated with these stimuli for 24 h were increased 13.3- and 1.3-fold by IL-1 alpha and 52.5- and 5.7-fold by TPA, respectively. By contrast, transforming growth factor alpha(TGF alpha), which also binds to EGF-receptor, enhanced their production as early as 2 h after treatment, indicating that growth factors that bind to EGF-receptor are likely to be involved in the translational enhancement of proMMP-3 and TIMP-1 mRNAs. EGF partially translocated cytoplasmic protein kinase C (PKC) to plasma membrane, but the PKC down-regulation induced by 100nM TPA did not diminish the EGF-mediated translational augmentation of proMMP-3 and TIMP-1 mRNAs. In contrast, the PKC inhibitor of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) effectively suppressed the translational regulation of proMMP-3 and TIMP-1 in a dose-dependent manner during the first 2-h treatment with EGF. These results suggest that EGF and TGF alpha, but not IL-1 alpha and TPA, specifically augment the translation of proMMP-3 and TIMP-1 mRNAs and accelerate their accumulation without modifying their transcripts during the first 1-2 h treatment of human uterine cervical fibroblasts. This translational augmentation is suggested to be mediated by a TPA-insensitive atypical PKC subclass in the PKC family.
我们之前报道过，在对人子宫颈成纤维细胞进行最初1小时的处理过程中，表皮生长因子（EGF）可增强前基质金属蛋白酶3（proMMP-3/前基质溶解素1）和金属蛋白酶组织抑制剂（TIMP）-1 mRNA的翻译（细野，T.等人，《欧洲生物化学学会联合会快报》，381，115 - 118，（1996年））。在本报告中，我们研究了白细胞介素1α（IL-1α）和12 - O - 十四烷酰佛波醇13 - 乙酸酯（TPA）这两种促MMPs和TIMP-1产生的强效刺激剂对proMMP-3和TIMP-1 mRNA翻译的影响。当用人子宫颈成纤维细胞用IL-1α或TPA处理2小时时，它们的翻译并未增强，而用这些刺激物处理24小时的细胞中，proMMP-3和TIMP-1 mRNA的稳态水平分别被IL-1α提高了13.3倍和1.3倍，被TPA提高了52.5倍和5.7倍。相比之下，同样与EGF受体结合的转化生长因子α（TGFα）在处理后2小时就增强了它们的产生，这表明与EGF受体结合的生长因子可能参与了proMMP-3和TIMP-1 mRNA的翻译增强。EGF使细胞质蛋白激酶C（PKC）部分转位到质膜，但100nM TPA诱导的PKC下调并未减弱EGF介导的proMMP-3和TIMP-1 mRNA的翻译增强。相反，1 - （5 - 异喹啉磺酰基）-2 - 甲基哌嗪二盐酸盐（H - 7）这种PKC抑制剂在与EGF最初2小时的处理过程中以剂量依赖的方式有效抑制了proMMP-3和TIMP-1的翻译调控。这些结果表明，在对人子宫颈成纤维细胞最初1 - 2小时的处理过程中，EGF和TGFα，而非IL-1α和TPA，特异性地增强了proMMP-3和TIMP-1 mRNA的翻译，并加速了它们的积累，而没有改变它们的转录本。这种翻译增强被认为是由PKC家族中对TPA不敏感的非典型PKC亚类介导的。
