Translational Augmentation of Pro-matrix Metalloproteinase 3 (Prostromelysin 1) and a Tissue Inhibitor of Metalloproteinases (TIMP)-1 mRNAs by Epidermal Growth Factor and Transforming Growth Factor .ALPHA., but not by Interleukin 1.ALPHA. or 12-O-Tetradecanoylphorbol 13-Acetate in Human Uterine Cervical Fibroblasts: The Possible Involvement of an Atypical Protein Kinase C.

HOSONO Tetsuji, ITO Akira, SATO Takashi, NAGASE Hideaki, MORI Yo

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 1α (IL-1α) 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-1α or TPA for 2 h, 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-1α and 52.5- and 5.7-fold by TPA, respectively. By contrast, transforming growth factor α (TGFα), 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 hte PKC down-regulation induced by 100 nM 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 trahslational 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 TGFα, but not IL-1α 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 stypical PKC aubclass in the PKC family.

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