Document Detail

Enhanced Gadd45 expression and delayed G2/M progression are p53-dependent in zinc-supplemented human bronchial epithelial cells.
MedLine Citation:
PMID:  20660093     Owner:  NLM     Status:  MEDLINE    
Zinc is an essential nutrient for humans; however, this study demonstrated for the first time that an elevated zinc status, created by culturing cells at optimal plasma zinc concentration attainable by oral zinc supplementation, is cytotoxic for normal human bronchial epithelial (NHBE) cells. p53 plays a central role in the modulation of cell signal transduction in response to the stress from DNA damage, hypoxia and oncogene activation. The present study was designed to determine whether the previously reported increased Gadd45 expression and delayed G2/M cell cycle progression in zinc-supplemented NHBE cells is p53-dependent, and to decipher the mechanisms responsible for the regulation of Gadd45 expressions by p53, and elucidate the Gadd45 functions in impaired cell growth and cell cycle progression in NHBE cells. Cells were cultured for one passage in different concentrations of zinc: <0.4 micromol/L (ZD) as severe zinc-deficient; 4 micromol/L (ZN) as normal zinc level in culture medium; 16 micromol/L (ZA) as normal human plasma zinc level; and 32 micromol/L (ZS) as the high end of plasma zinc attainable by oral supplementation. Inhibition of cell growth and upregulation of p53 mRNA and protein expression were observed in ZS cells. Most importantly, ZS treatment also enhanced Gadd45 nuclear protein level and promoter activity, decreased CDK1-Cyclin B1 level and delayed G2/M cell cycle progression. These changes were normalized to those observed in ZN by treating ZS cells with Pifitherin, an inhibitor of p53 transactivation activity. Thus, our findings support the p53 dependency of the Gadd45-CDK1/Cyclin B1-G2/M cell cycle progression pathway in ZS NHBE cells.
Rita S M Shih; Stephen H K Wong; Norberta W Schoene; Jun Jun Zhang; Kai Y Lei
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Experimental biology and medicine (Maywood, N.J.)     Volume:  235     ISSN:  1535-3699     ISO Abbreviation:  Exp. Biol. Med. (Maywood)     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-27     Completed Date:  2010-10-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100973463     Medline TA:  Exp Biol Med (Maywood)     Country:  England    
Other Details:
Languages:  eng     Pagination:  932-40     Citation Subset:  IM    
Department of Nutrition and Food Science, University of Maryland, College Park, 20742, USA.
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MeSH Terms
Benzothiazoles / pharmacology
Bronchi / cytology*
CDC2 Protein Kinase / metabolism
Cells, Cultured
Cyclin B1 / metabolism
Dose-Response Relationship, Drug
Epithelial Cells / cytology,  drug effects,  metabolism*
G2 Phase / drug effects*
Gene Expression Regulation / drug effects
Intracellular Signaling Peptides and Proteins / genetics*,  metabolism
Mitosis / drug effects*
RNA, Messenger / genetics,  metabolism
Toluene / analogs & derivatives,  pharmacology
Tumor Suppressor Protein p53 / genetics,  metabolism*
Zinc / pharmacology*
Reg. No./Substance:
0/Benzothiazoles; 0/Cyclin B1; 0/GADD45 protein; 0/Intracellular Signaling Peptides and Proteins; 0/RNA, Messenger; 0/Tumor Suppressor Protein p53; 0/pifithrin; 108-88-3/Toluene; 7440-66-6/Zinc; EC Protein Kinase

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