Abstract
One of the 14-3-3 protein isoforms, 14-3-3epsilon, was previously shown to be increased during skin aging. We suggest here a possible role for the 14-3-3epsilon protein in skin aging by providing evidence that 14-3-3epsilon increases the expression of the matrix-metalloproteinase (MMP)-2 gene in NIH3T3 fibroblast cells. Expression of the 14-3-3epsilon gene in NIH3T3 cells primarily up-regulated the expression of the MMP-2 gene at the transcriptional level by inducing specific DNA binding proteins bound to an upstream region of the MMP-2 promoter from -1,629 to -1,612. Inhibition of endogenous 14-3-3epsilon gene expression by RNA interference also decreased endogenous MMP-2 gene expression. Furthermore, up-regulation of the MMP-2 gene by 14-3-3epsilon was suppressed by expression of a dominant-negative mutant of p38 MAP kinase. These findings strongly suggest that increased expression of 14-3-3epsilon contributes to remodeling of extracellular matrix in skin through increasing MMP-2 gene expression via p38 MAP kinase signaling.
Highlights
Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases that collectively degrade several extracellular matrix (ECM) constituents
Among the MMPs, it was recently reported that the activation of gelatinases, including MMP-2 and MMP-9, played important roles in ultraviolet-induced skin aging in hairless mice (Inomata et al, 2003) and MMP-2 was expressed in human dermal fibroblasts (Scharffetter et al, 1991)
We propose here that 14-3-3ε can increase the expression of the MMP-2 gene by induction of specific DNA binding proteins bound to a distinct region from -1,629 to -1,612 of the MMP-2 promoter via p38 dominant negative p38 MAPK (MAPK) signaling, which eventually leads to alterations of ECM components
Summary
Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases that collectively degrade several extracellular matrix (ECM) constituents. Because MMPs are primarily responsible for ECM turnover and connective tissue remodeling, accumulating evidence indicates that an imbalance in the expressions of MMPs under pathological conditions are related to human diseases, including dermal fibrosis, skin aging and cancer (Fisher et al, 1996; Ghahary et al, 1996; Nagase and Woessner, 1999; Brinckerhoff and Matrisian, 2002; Rittie and Fisher, 2002). Among the MMPs, it was recently reported that the activation of gelatinases, including MMP-2 and MMP-9, played important roles in ultraviolet-induced skin aging in hairless mice (Inomata et al, 2003) and MMP-2 was expressed in human dermal fibroblasts (Scharffetter et al, 1991)
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