title: Possible involvement of NEDD4 in keloid formation; its critical role in fibroblast proliferation and collagen production.
abstract: Keloid represents overgrowth of granulation tissue, which is characterized by collection of atypical fibroblasts with excessive deposition of extracellular matrix components, after skin injury, but its etiology is still largely unknown. We recently performed genome-wide association study (GWAS) of keloid and identified NEDD4 to be one of candidate molecules associated with keloid susceptibility. Here we demonstrate a possible mechanism of NEDD4 involvement in keloid formation through enhancement of the proliferation and invasiveness of fibroblasts as well as upregulation of type 1 collagen expression. Activation of NEDD4 affected subcellular localization and protein stability of p27 which was implied its critical role in contact inhibition. It also induced accumulation of β-catenin in the cytoplasm and activated the TCF/β-catenin transcriptional activity. Furthermore, NEDD4 upregulated expressions of fibronectin and type 1 collagen and contributed to the excessive accumulation of extracellular matrix. Our findings provide new insights into mechanism developing keloid and can be applied for development of a novel treatment for keloid.
authors: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
authors: Suyoun
authors: S
authors: Chung
authors: Mitsuko
authors: M
authors: Nakashima
authors: Hitoshi
authors: H
authors: Zembutsu
authors: Yusuke
authors: Y
authors: Nakamura
mesh_terms: D000818:Animals; D002450:Cell Communication; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000096:biosynthesis*; D024042:Collagen Type I / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007627:Keloid / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D041681:NIH 3T3 Cells; D000075702:Nedd4 Ubiquitin Protein Ligases; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D056827:Endosomal Sorting Complexes Required for Transport; D005353:Fibronectins; D051176:beta Catenin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003094:Collagen; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase