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      Prostacyclin Inhibits the Production of MMP-9 Induced by Phorbol Ester through Protein Kinase A Activation, but Does Not Affect the Production of MMP-2 in Human Cultured Mesangial Cells

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          Background/Aims: The imbalance between degradation and synthesis of the glomerular extracellular matrix (ECM) causes glomerular sclerosis in various types of glomerulonephritis. We investigated the effect of prostacyclin, which is an inflammatory mediator, on the production of matrix metalloproteinase (MMP)-9 and MMP-2 in human cultured mesangial cells. The synthesis of Jun proteins and Ets-1 proteins, which are related with MMP-9 gene, was also studied. Methods: The production of MMP-9 and MMP-2 was investigated by gelatin zymography. Western blotting was undertaken to analyze the protein synthesis of Jun and Ets-1. Results: Prostacyclin inhibited the production of MMP-9 induced by phorbol ester. The inhibitory effect by prostacyclin was reversed in part by the pretreatment with an inhibitor of protein kinase A, such as H-89. Forskolin also inhibited the production of MMP-9. The production of MMP-2 was constitutionally seen and was not influenced by prostacyclin and forskolin. The synthesis of Jun protein augmented by phorbol ester was suppressed by prostacyclin. Ets-1 protein was constitutionally synthesized and was not affected by phorbol ester and prostacyclin. Conclusion: Prostacyclin plays an important role in inflammatory glomerular disorders by regulating the metabolism of ECM. The production of MMP-9 and MMP-2 may be under the different control pathways.

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          Most cited references 8

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          Nitric oxide mediates network oscillations of olfactory interneurons in a terrestrial mollusc.

           A Gelperin (1994)
          The interneuronal messenger nitric oxide (NO) may play a central role in the processing of olfactory information. Several circuit elements in the mammalian olfactory bulb contain NO synthase or its functional equivalent, NADPH diaphorase. The effects of NO on cellular excitability or circuit dynamics in the olfactory bulb are unknown, although NO effects on other rhythmic cells and circuits have been described. I have studied the role of NO in central olfactory processing using the procerebral (PC) lobe, the major central site of odour processing in terrestrial molluscs. As in the mammalian olfactory bulb during odour stimulation, the basic dynamics of electrical activity in the molluscan PC lobe is an oscillation. Here I report an obligatory role for NO in the oscillatory dynamics of the PC lobe of Limax maximus. Nitric oxide mediation of the olfactory oscillation may relate to the highly developed odour sensitivity and odour-learning ability of Limax.
            • Record: found
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            The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation.

            Cell transformation by oncogenes leads to changes in gene expression. A key event in this process seems to be activation of the transcription factors AP-1 and PEA 3. Their synergistic activities are required for efficient activation of transcription from different promoters by many different oncogenes, serum growth factors and the tumour promoter TPA. We show here that the products of the ets-1 and -2 proto-oncogenes, whose biological function was previously unknown, are transcription factors that activate transcription through the PEA 3 motif. The p68c-ets-1 protein specifically binds to DNA and contains a transcriptional activation domain. The ets-like gene family therefore seems to encode a new family of transcription factors, apparently unrelated to other transcription factors. The p68c-ets-1 protein cooperates with c-Fos and c-Jun (components of AP-1) for activation of transcription from the oncogene-responsive domain of the polyoma enhancer, indicating that combined activity of all three oncoproteins could be involved in the response of cells to growth stimuli.
              • Record: found
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              Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences.

               E Lengyel,  M Seiki,  H. Sato (1996)
              The 92-kDa type IV collagenase (92-kDa gelatinase B also referred to as MMP-9), which plays a critical role in extracellular matrix degradation, is regulated by growth factors that mediate their effects through the ras proto-oncogene. The current study was undertaken to determine the transcriptional requirements for the induction of 92-kDa gelatinase B expression by an activated ras oncogene. Transfection of OVCAR-3 cells with an expression vector encoding an activated Ha-ras increased 92-kDa gelatinolytic activity and stimulated (over 10-fold) the activity of a CAT reporter driven by 670 nucleotides of 5' flanking sequence of the 92-kDa gelatinase B gene. Transient assays using a CAT reporter driven by 5' deleted fragments of the 92-kDa gelatinase B promoter indicated that a region spanning -634 to -531 was required for optimal induction of the promoter. The individual deletion, or mutation, of a PEA3/ets (-540) motif, AP-1 sites (-533, -79), a NF-kappa B (-600) consensus sequence, and a GT box (-52) substantially reduced the activation of the promoter by ras. An expression vector encoding the PEA3 transcription factor caused a 3-fold stimulation of the wild type but not the PEA3/ets-deleted 92-kDa gelatinase B promoter. Coexpression of a dominant negative c-jun antagonized the ras-dependent stimulation of the 92-kDa gelatinase B promoter-driven CAT reporter. The signaling pathway mediating the induction of 92-kDa gelatinase B promoter activity by ras was examined. The expression of a phosphatase (CL100) which inactivates multiple mitogen-activate protein kinase members abrogated the stimulation of 92-kDa gelatinase B promoter activity by ras. However, the expression of a kinase-deficient mitogen-activated protein kinase kinase 1 (MEK1) did not prevent activation of the 92-kDa gelatinase B promoter by ras and a constitutively activated c-raf expression vector was insufficient for 92-kDa gelatinase B promoter activation. Thus, the stimulation of the 92-kDa gelatinase B promoter by ras requires multiple elements including closely spaced PEA3/est and AP-1 sites and is MEK1-independent.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                24 January 2001
                : 24
                : 1
                : 18-26
                Departments of aPediatrics and bPathology, Shinshu University School of Medicine, Matsumoto, Japan
                54201 Kidney Blood Press Res 2001;24:18–26
                © 2001 S. Karger AG, Basel

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                Figures: 7, References: 35, Pages: 9
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