TIMP-2 growth-stimulatory activity: a concentration- and cell type-specific response in the presence of insulin.
In addition to proteinase-inhibitory activities, growth-stimulatory activities have been described for all three known members of the tissue inhibitors of the metalloproteinase (TIMP) family, TIMP-1, TIMP-2, and ChIMP-3, believed to be the chicken homologue of TIMP-3. However, the mechanism by which the TIMPs stimulate cell growth is unclear. In this report we have demonstrated that rTIMP-2 was growth-stimulatory for human foreskin fibroblasts (HSF4, HSF43, HS68), lung adenocarcinoma cells (A549), human melanoma cells (WM115), and the Burkitt's lymphoma cell line RAMOS, and this stimulatory response was concentration-dependent, with the greatest stimulation occurring a 10-30 pM rTIMP-2 in [3H]thymidine incorporation assays and at 20-100 pM in cell growth assays. Normal human colon (18Co) and lung (37Lu) fibroblasts showed no response to rTIMP-2. [3H]Thymidine incorporation was inhibited by rTIMP-2 treatment in the nonadherent cell line HL60. These studies also demonstrated that for the cell types tested, TIMP-2 alone was insufficient for a growth stimulatory response requiring, at a minimum, the presence of insulin. In the absence of any "co-factor(s)," such as insulin, TIMP-2 treatment was inhibitory.
Nemeth
J A
JA
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Rafe
A
A
Steiner
M
M
Goolsby
C L
CL
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2
D007328:Insulin; D011480:Protease Inhibitors; D011506:Proteins; D011994:Recombinant Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2