Feb. 26 - High Zinc Status in Lung Cells Slows Growth and Induces
DNA Damage-Induced Gene Expression
Researchers at the University of Maryland at
College Park have discovered that Normal Human Bronchial Epithelial
(NHBE) cells cultured in medium with elevated zinc level, at
the high end of plasma zinc attainable by oral supplementation,
demonstrated inhibition of cell growth, up-regulation of growth
arrest and DNA damage-induced gene (Gadd45) mRNA and protein
expression, and blockage of G2/M cell cycle progression. The
research, published in the March 08 issue of the Experimental
Biology and Medicine, demonstrated that the essential
nutrient zinc, at elevated physiologic level, is capable of
inducing stress responsive genes in the NHBE cells. NHBE cells
function as a protective airway barrier and are representative
of the cell population during lung tissue transformation and
are considered to be progenitor cells for human bronchial cancer.
Gadd45 is ubiquitously expressed in response
to genotoxic agents, and is involved in many biological processes
related to the maintenance of genomic stability and apoptosis.
Over expression of Gadd45 was found to induce G2/M cell cycle
arrest. The importance of Gadd45 in G2/M regulation was further
supported by findings of the inability of cells from Gadd45
knockout mice to arrest at the G2/M phase after exposure to
UV radiation.
In addition, a functional association between
stress-activated mitogen-activated protein kinase p38 pathway
and Gadd45 in response to environmental stresses has been established
in past studies. Moreover, the dependence of Gadd45 induction
for the normal function of the tumor suppressor gene p53, which
plays an important role in the maintenance of genomic fidelity
by controlling cell cycle checkpoints and apoptotic processes
following cell exposure to genotoxic stress, is well established.
Furthermore, in response to DNA damage, Gadd45 was found to
contribute to the stability of p53.
The research team, led by David K. Y. Lei, a
professor of Nutrition, and Rita S. M. Shih, a recent doctoral
graduate, designed the study to determine the influence of zinc
status on Gadd45 expression and cell cycle progression in NHBE
cells, and to decipher the molecular mechanism(s) exerted by
the suppression of Gadd45 expression on cell growth and cell
cycle progression in this normal human cell type.
"Inhibition of cell growth, up-regulation
of Gadd45 mRNA and protein expression, and blockage of G2/M
cell cycle progression were observed in NHBE cells cultured
in high zinc medium - the zinc supplemented (ZS) cells "
said Lei. " The siRNA-mediated knocking down of Gadd45
was found to relieve G2/M blockage in ZS cells, which indicated
that the blockage was Gadd45 dependent. Moreover, the enhanced
phosphorylation of p38 and p53 (ser15) observed in ZS cells
was normalized after suppression of Gadd45 by siRNA, implicating
that the enhanced phosphorylation of these proteins was Gadd45
dependent". Thus, the researchers demonstrated for the
first time that an elevated zinc status modulated the p53 and
p38 signal transduction pathways to produce a delay at G2/M
during cell cycle progression in NHBE cells.
Dr. Steven R. Goodman, Editor-in-Chief of Experimental
Biology and Medicine said "This study on
the molecular and cellular response of NHBE cells to a high
zinc challenge may have important implications for conditions
such as industrial exposure and extensive usage of zinc supplementation
in animal production and in humans."
Source: Society for Experimental Biology
and Medicine
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