title: Smad-induced alterations of matrix metabolism by a myristoyl tetra peptide.
abstract: Regulation of extracellular matrix (ECM) components is essential for tissue homeostasis and function. We screened a small peptide that induces ECM protein synthesis for its usefulness in protecting keratinocytes. In this report, we demonstrate that myristoyl tetrapeptide Ala-Ala-Pro-Val (mAAPV) stimulates the expression of ECM proteins and inhibits the expression of metalloproteinases (MMPs) that degrade ECM proteins in Hs68 human fibroblast cells. In order to elucidate the underlying molecular mechanisms for the effects of mAAVP, we investigated the changes in gene expression in the presence of mAAPV using a cDNA microarray. Treatment with mAAPV resulted in decreased expression of MMP-related genes such as MMP1, MMP3, TIMP1 and TIMP3 and increased expression of collagen genes, including COL1A1, COL1A2, COL3A1, COL5A1 and COL6A3. The pattern of gene expression regulated by mAAPV was very similar to that of gene expression induced by transforming growth factor (TGF)-β, indicating that the TGF-β signaling pathway is crucial for simultaneous activation of several ECM-related genes by mAAPV. We examined whether the activation of SMAD, a downstream protein of TGF-β receptor, is involved in the signal transduction pathway induced by mAAPV. The results demonstrate that mAAVP directly activates SMAD2 and induces SMAD3 to bind to DNA. In conclusion, our results demonstrate that mAAPV both enhances the expression of collagen and inhibits its degradation via production of protease inhibitors that prevent enzymatic breakdown of the ECM. The results suggest that mAAPV would be a useful ECM-protecting agent.
authors.affiliation: Department of Applied Chemistry, Dongduk Women's University, Seoul, Republic of Korea.
authors.forename: Haeyoung
authors.initials: H
authors.lastname: Kwon
authors.forename: Yun Sub
authors.initials: YS
authors.lastname: Lee
authors.forename: Myung Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Min Youl
authors.initials: MY
authors.lastname: Chang
authors.forename: Bo Mi
authors.initials: BM
authors.lastname: Won
authors.forename: Byung Suk
authors.initials: BS
authors.lastname: Jin
authors.forename: Seyeon
authors.initials: S
authors.lastname: Park
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011347:Procollagen / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D010455:Peptides; D011347:Procollagen; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D020781:Matrix Metalloproteinase 1
keywords: SMAD; microarray; myristoyl tetrapeptide; procollagen; transforming growth factor-β signaling