Tissue inhibitor of metalloproteinase-1 promotes NIH3T3 fibroblast proliferation by activating p-Akt and cell cycle progression

Mol Cells. 2011 Mar;31(3):225-30. doi: 10.1007/s10059-011-0023-9. Epub 2011 Jan 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle*
  • Cell Proliferation*
  • Chromones / pharmacology
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Fibroblasts / cytology*
  • Fibroblasts / physiology
  • Fibrosis
  • Mice
  • Morpholines / pharmacology
  • NIH 3T3 Cells
  • Oncogene Protein v-akt / metabolism*
  • Phosphorylation
  • Recombinant Proteins / metabolism*
  • Signal Transduction / drug effects
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*


  • Cdkn1a protein, mouse
  • Cdkn1b protein, mouse
  • Chromones
  • Cyclin-Dependent Kinase Inhibitor p21
  • Morpholines
  • Recombinant Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Oncogene Protein v-akt