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Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. Paper-1566726. Neither AP-1 nor NF-kappaB was therefore sufficient on its own for synergistic regulation.
Using electromobility shift assays, binding to the AP-1 site was only slightly increased by growth factors and cytokines.
NF-kappaB binding was rapidly induced by IL-1alpha or TNF-alpha but was neither induced nor potentiated by bFGF or PDGF. Paper-1566726.
Activation of NF-kappaB binding by inflammatory cytokines was therefore necessary but not sufficient for synergistic upregulation of MMP-9. Paper-1566726.
Matrix metalloproteinase (MMPs) enzymes are implicated in matrix remodelling during proliferative inflammatory processes including wound healing. Paper-1566726.
The synergistic interaction between growth factors and cytokines implies that basement membrane remodelling is maximal physiologically when both are present together.
Using a recently developed adenovirus that overexpresses the inhibitory subunit, IkappaB alpha, we demonstrated an absolute requirement for NF-kappaB in upregulation of MMP-9. Paper-1566726.
The signalling pathways mediating this synergistic regulation are not understood, although analysis of the MMP-9 promoter has identified an essential proximal AP-1 element and an upstream nuclear factor kappa-B (NF-kappaB) site. Paper-1566726.
We report here synergistic upregulation of MMP-9 protein and mRNA by platelet-derived growth factor ( PDGF) or basic fibroblast growth factor ( bFGF) in combination with interleukin-1alpha (IL-1alpha) or tumour necrosis factor-alpha ( TNF-alpha) in primary rabbit and human dermal fibroblasts. Paper-1566726.
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