title: Tissue inhibitor of metalloproteinase-1 promotes NIH3T3 fibroblast proliferation by activating p-Akt and cell cycle progression.
abstract: Tissue inhibitor of metalloproteinase-1 (TIMP-1) plays various roles in cell growth in different cell types. However, few studies have focused on TIMP-1's effect on fibroblast cells. In this study, we investigated the effects of TIMP-1 overexpression on NIH3T3 fibroblast proliferation and potential transduction signaling pathways involved. Overexpression of TIMP-1, by transfection of the pLenti6/V5-DESTTIMP-1 plasmid, significantly promoted NIH3T3 proliferation as determined by the BrdU array. Neither 5 nor 15 nM GM6001 (matrix metalloproteinase system inhibitor) affected NIH3T3 proliferation, but 45 nM GM6001 inhibited proliferation. TIMP-1 overexpression activated the p-Akt pathway, but not the p-ERK or p-p38 pathway. In TIMP-1-transfected cells, cyclinD1 was upregulated and p21CIP1 and p27(KIP1) were downregulated, which promoted cell entry into the S and G2/M phases. The PI3-K inhibitor LY294002 abolished the TIMP-1-induced effects. Overexpression of intracellular TIMP-1 stimulated NIH3T3 fibroblast proliferation in a matrix metalloproteinase (MMP)-independent manner by activating the p-Akt pathway and related cell cycle progression.
authors.affiliation: Department of Nephrology, Kidney Center and Key Lab of People's Liberation Army (PLA), General Hospital of PLA, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Shuxin
authors.initials: S
authors.lastname: Liu
authors.forename: Shujia
authors.initials: S
authors.lastname: Zhang
authors.forename: Guangyan
authors.initials: G
authors.lastname: Cai
authors.forename: Hongwei
authors.initials: H
authors.lastname: Jiang
authors.forename: Huabin
authors.initials: H
authors.lastname: Su
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Li
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D005355:Fibrosis; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D041681:NIH 3T3 Cells; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D002867:Chromones; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009025:Morpholines; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051058:Oncogene Protein v-akt