Lysyl oxidase oxidizes basic fibroblast growth factor and inactivates its mitogenic potential.
Lysyl oxidase (LO) plays a central role in the crosslinking of collagen and elastin in the extracellular matrix. Here we demonstrate that basic fibroblast growth factor (bFGF), a polypeptide which regulates proliferation, differentiation, and migration of a variety of cell types, is a substrate of LO. The oxidation of lysine residues in bFGF by LO resulted in the covalent crosslinking of bFGF monomers to form dimers and higher order oligomers and dramatically altered its biological properties. Both the mitogenic potential and the nuclear localization of bFGF were markedly inhibited in the Swiss 3T3 cells upon its oxidation by LO. NIH 3T3 IgBNM 6-1 cells (6-1 cells) overexpress bFGF which participates in an autocrine mechanism accounting for the transformation of these cells into a tumorigenic state. Exposure of the 6-1 cells to nanomolar concentrations of LO in culture oxidized lysine and generated crosslinkages in bFGF within the cell and markedly reduced proliferative rates. The lack of LO expression has been correlated with hyperproliferative cell growth, while this enzyme has been identified as a suppressor of ras-induced tumorigenesis. The present results illustrate a mechanism by which LO can depress normal and transformed cell growth.
Li
Wande
W
Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 02118, USA.
Nugent
Matthew A
MA
Zhao
Yinzhi
Y
Chau
Anne N
AN
Li
Sandy J
SJ
Chou
Iih-Nan
IN
Liu
Guanmei
G
Kagan
Herbert M
HM
D016475:3T3 Cells; D000818:Animals; D001011:Aorta / Q000201:enzymology; D015153:Blotting, Western; D002417:Cattle; D002453:Cell Cycle; D002455:Cell Division; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D013997:Time Factors
D003432:Cross-Linking Reagents; D016222:Fibroblast Growth Factor 2; D006861:Hydrogen Peroxide; D008249:Protein-Lysine 6-Oxidase; D010100:Oxygen