The upstream events leading to Smad7 overexpression in the herein described direct co culture model of CCD 1068SK AZD9291 EGFR inhibitor fibroblasts and MDA MB 231 tumour cells has not yet been determined. Our results suggest that regulation oc curs at the transcriptional level as Smad7 mRNA levels were found to be significantly increased. Previous studies investi gating Smad7 regulation have mainly focussed on the effect of various cytokines on Smad7 expression. Those found to increase Smad7 levels include IFN via JAKStat signalling and IL1B via either JNK or NFB activation. How ever, since Smad7 overexpression Inhibitors,Modulators,Libraries only occurred in fibro blasts directly co cultured with tumour cells, this suggests that cell surface factors may be involved in regulation of Smad7. Further investigations would need to be per formed to determine these factors.
Investigating the intracellular signalling events leading to CCN2 and type I collagen down regulation, we found that tumour cell mediated up regulation of Smad7 negatively af fected the MEKERK pathway. However, Inhibitors,Modulators,Libraries inhibition of this pathway Inhibitors,Modulators,Libraries had more dramatic effects on CCN2 expression while type I collagen was only slightly decreased. Previous studies have suggested that RasMEKERK signalling posi tively regulates CCN2 promoter activity and is required for basal CCN2 promoter activity. However, the effect of MEKERK signalling on type I collagen gene ex pression is not clear. Some studies suggest that MEKERK activation negatively regulates type I collagen expression. However, addition of IL 4 or IL 13 to dermal fibro blasts also increases type I collagen promoter activity in an ERK dependent manner.
The effect of MEKERK sig nalling on type I collagen gene expression therefore appears to be dependent on interactions with other signalling path ways and on the cell context. Recent studies have shown that TGFB mediated up regulation of both CCN2 and type I collagen in fibroblasts requires activation of Alk1 Smad1 and downstream ERK12 signalling Inhibitors,Modulators,Libraries and that the Inhibitors,Modulators,Libraries association of CCN2 with B3 integrin is re quired for TGFB mediated Smad1 phosphorylation. Si lencing Smad1 gene expression resulted in a decrease in the expression of both TGFB stimulated CCN2 and type I colla gen gene expression as well as basal type I collagen gene ex pression. CCN2 has, in turn, been shown to activate ERK12 signalling by adhesion to the alpha1beta6 integrin receptor or syndecan 4, a heparin sulphate proteoglycan.
The MEKERK signalling pathway therefore appears to play an important role in positively regulating CCN2 ex pression which, in turn, leads to further increased activation screening library of MEKERK in a positive feedback loop. Deregulation of the MEKERK signalling pathway in fibroblasts close to or adjacent to tumour cells could therefore have important im plications for ECM synthesis and homeostasis.
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