Metallothionein is required for zinc‐induced expression of the macrophage colony stimulating factor gene

Abstract

Macrophage colony stimulating factor (M-CSF) plays an important role in the proliferation and differentiation of mononuclear phagocytes. The present study investigates the effect of zinc on M-CSF expression in MC3T3-E1 and L929 cells. Zinc dose-dependently increased M-CSF mRNA levels. The time-course of zinc-induced M-CSF mRNA expression peaked at 6 h. Stability studies of mRNA using actinomycin D revealed that zinc does not affect M-CSF mRNA stability. We examined the function of the M-CSF gene promoter using a luciferase reporter assay. A construct containing the -467/+39 region of the promoter was upregulated by zinc. In the presence of cycloheximide, zinc did not induce a greater increase in the M-CSF mRNA than cycloheximide alone. To confirm the effect of MT on M-CSF mRNA expression, mouse lung fibroblasts (MLFs) were prepared from MT+/+ and MT-/- mice. Zinc induced an increase in the expression of M-CSF in MT+/+ MLFs, but this response was not evident in MT-/- MLFs. Moreover, overexpression of MT upregulated M-CSF mRNA expression as well as M-CSF secretion. Our findings suggest that MT expression mediates zinc regulation of M-CSF gene expression at the transcriptional level.

Up-regulation by zinc of FGF-2-induced VEGF release throughenhancing p44/p42 MAP kinase activation in osteoblasts

“…It has been reported that zinc enhances the activity of 1,25-dihydroxyvitamin D 3 -dependent promoters and the anabolic effect of insulin-like growth factor-I (Matsui and Yamaguchi, 1995;Lutz et al, 2000). In addition, zinc reportedly induces expression of macrophage colony stimulating factor gene in osteoblasts (Kanekiyo et al, 2002). Based on these findings, it is probable that zinc-enhanced VEGF release from osteoblasts plays a pivotal role in the process of bone remodeling via up-regulating the proliferation of capillary endothelial cells.…”

Effect of Zinc Upon Human and Murine Cell Viability and Differentiation

“…It participates with RNA and DNA polymerases and is needed during G1/S transition. This suggests its participation in cellular proliferation regulation [28][29][30].…”

Function of Metallothionein in Gene Expression and Signal Transduction: Newly Found Protective Role of Metallothionein

“…75) Zinc-induced expression of macrophage colonystimulating factor in MC3T3-E1 and L929 cells required MT-mediated NF-κB activation. 76) On the other hand, NF-κB is a redox-regulated TF, and MT may control intracellular redox status. Cytosolic MT may act as a negative regulator of NF-κB ac-tivity.…”