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ORIGINAL RESEARCH ARTICLE

Suppression of Gadd45 Alleviates the G2/M Blockage and the Enhanced Phosphorylation of p53 and p38 in Zinc Supplemented Normal Human Bronchial Epithelial Cells

Rita S. M. Shih^*, Stephen H. K. Wong^*, Norberta W. Schoene and Kai Y. Lei^*,1

^* Department of Nutrition and Food Science, University of Maryland, College Park, Maryland 20742; and Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, Maryland 20705

To whom requests for reprints should be addressed at ¹ Department of Nutrition and Food Science, 0121 Skinner Building, College Park, MD 20742. E-mail: dlei{at}umd.edu

An adequate zinc status is essential for optimal cellular functions and growth. Yet, excessive zinc supplementation can be cytotoxic and can impair cell growth. Gadd45 plays a vital role as cellular stress sensor in the modulation of cell signal transduction in response to stress. The present study was designed to determine the influence of zinc status on Gadd45 expression and cell cycle progression in zinc deficient and supplemented normal human bronchial epithelial (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 cell type. Cells were cultured for one passage in different concentration of zinc: <0.4 µM (ZD) as severe zinc deficient; 4 µM as normal zinc level in culture medium; 16 µM (ZA) as normal human plasma zinc level; and 32 µM (ZS) as the high end of plasma zinc attainable by oral supplementation. Inhibition of cell growth, upregulation of Gadd45 mRNA and protein expression, and blockage of G2/M cell cycle progression were observed in ZS cells. In contrast, little or no changes in these parameters were seen in ZD cells. 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) in ZS cells was normalized after suppression of Gadd45 by siRNA, implicating that the enhanced phosphorylation of these proteins was Gadd45 dependent. Thus, we demonstrated for the first time that an elevated zinc status modulated signal transduction to produce a delay at G2/M during cell cycle progression in NHBE cells.

Key Words: Gadd45 • p38 • p53 • siRNA • G2/M • zinc supplementation

Related articles in EBM:

Zinc Supplementation Inhibits Cell Growth and Increases the DNA Damage-Induced Gene (Gadd45) Expression in Human Bronchial Epithelial Cells in Culture

EBM 2008 233: viii. [Full Text]  

This article has been cited by other articles:

				S. H. K. Wong, R. S. M. Shih, N. W. Schoene, and K. Y. Lei Zinc-induced G2/M blockage is p53 and p21 dependent in normal human bronchial epithelial cells Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1342 - C1349. [Abstract] [Full Text] [PDF]