Intracellular lysyl oxidase: effect of a specific inhibitor on nuclear mass in proliferating cells.
LOX, the principal enzyme involved in crosslinking of collagen, was the first of several lysyl oxidase isotypes to be characterized. Its active form was believed to be exclusively extracellular. Active LOX was later reported to be present in cell nuclei; its function there is unknown. LOX expression opposes the effect of mutationally activated Ras, which is present in about 30% of human cancers. The mechanism of LOX in countering the action of Ras is also unknown. In the present work, assessment of nuclear protein for possible effects of lysyl oxidase activity led to the discovery that proliferating cells dramatically increase their nuclear protein content when exposed to BAPN (beta-aminopropionitrile), a highly specific lysyl oxidase inhibitor that reportedly blocks LOX inhibition of Ras-induced oocyte maturation. In three cell types (PC12 cells, A7r5 smooth muscle cells, and NIH 3T3 fibroblasts), BAPN caused a 1.8-, 1.7-, and 2.1-fold increase in total nuclear protein per cell, respectively, affecting all major components in both nuclear matrix and chromatin fractions. Since nuclear size is correlated with proliferative status, enzyme activity restricting nuclear growth may be involved in the lysyl oxidase tumor suppressive effect. Evidence is also presented for the presence of apparent lysyl oxidase isotype(s) containing a highly conserved LOX active site sequence in the nuclei of PC12 cells, which do not manufacture extracellular lysyl oxidase substrates. Results reported here support the hypothesis that nuclear lysyl oxidase regulates nuclear growth, and thereby modulates cell proliferation.
Saad
Fawzy A
FA
Laboratory for the Study of Skeletal Disorders and Rehabilitation, Department of Orthopedics, Children's Hospital Boston, 300 Longwood Avenue EN926, Boston, MA 02115, USA.
Torres
Marie
M
Wang
Hao
H
Graham
Lila
L
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D002453:Cell Cycle; D002467:Cell Nucleus / Q000201:enzymology*; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D016716:PC12 Cells; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats
D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D000629:Aminopropionitrile; D004247:DNA; D008249:Protein-Lysine 6-Oxidase