title: Feedback regulation of the α2(1) collagen gene via the Mek-Erk signaling pathway.
abstract: The extracellular matrix (ECM) provides the microenvironment that is pivotal for cell growth, motility, attachment, and differentiation. Advances in cell culture techniques have led to the development of cell-derived ECM model systems that are more reflective of the in vivo architecture of the ECM in tissue. In this study, a fibroblast-derived ECM (fd-ECM) was used to study the feedback regulation of type I collagen synthesis in fibroblasts. Fibroblasts plated on a preformed fd-ECM showed a significant decrease in the production of type I collagen and pro-α2(1) collagen mRNA compared to cells grown in the absence of a matrix. Function-blocking antibodies showed that this downregulation of type I collagen gene expression is mediated via α2β1 integrin. The use of several kinase inhibitors and a dominant negative ras construct (N17Ras) showed that the matrix-mediated downregulation of COL1A2 occurs via Ras-dependent activation of the MEK/ERK signaling pathway. Deletion analysis of the COL1A2 promoter implicated the region between -375 and -107 as containing a potential matrix responsive element. The use of Sp1 siRNA demonstrated that Sp1 is an important mediator of this feedback inhibition. This study provides some new insights into the feedback regulation of COL1A2 gene expression.
authors: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Wernher and Beit Building (South), UCT Campus, Anzio Road, Observatory 7925, Cape Town, South Africa.
authors: Kevin
authors: K
authors: Dzobo
authors: Virna D
authors: VD
authors: Leaner
authors: M Iqbal
authors: MI
authors: Parker
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D039201:Integrin alpha3beta1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D038982:Integrin alpha2beta1; D039201:Integrin alpha3beta1; D016329:Sp1 Transcription Factor; D018631:ras Proteins