|Lei, K. Y.|
Submitted to: Experimental Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/30/2006
Publication Date: 5/1/2006
Citation: Alshatni, A.A., Han, C.T., Schoene, N.W., Lei, K.Y. 2006. Nuclear accumulations of p53 and Mdm2 are accompanied by reductions in c-Abi and p 300 in zinc-depleted human hepatoblastoma cells. Experimental Biology and Medicine(Maywood). 231(5):611-618. Interpretive Summary: Zinc, an essential micronutrient, is an integral part of many proteins required for normal cell function. Marginal zinc deficiencies occur within segments of the U.S. population and contribute to inadequate cellular responses to stresses. Such poor responsiveness can lead to diverse pathologies ranging from enhanced tumor growth, reduced wound healing, and improper immune function. Critical sites where zinc acts to control cellular function need to be more clearly identified to provide a sound basis for defining what is an adequate intake to maintain health. The experimental approach used was to grow cells in cultures containing amounts of zinc that duplicate known human consumption patterns. These included a deficient diet, a normal diet, and a super-adequate diet. Cells grown in the zinc deficient culturing media where shown to have irregular packing of regulatory proteins in the nuclei compared to cells exposed to normal and higher amounts of zinc. These differences help to explain why the zinc-deficient cells are more susceptible to stresses. The results expand on information about the role of zinc in preserving the health of the cell and, ultimately, that of the individual. This knowledge will benefit those working in the life sciences - nutritionists, molecular and cell biologists, immunologists, and oncologists - who wish to gain deeper insights into the mechanisms of zinc action.
Technical Abstract: The influence of zinc status on the expression of proteins that may be involve in the stability of p53, the human tumor suppressor gene product, was examined in hepatoblastoma (HepG2) cells. Cells were cultured in ZD0.2, ZD0.4, ZN, ZA, or ZS medium, which contained 0.2, 0.4, 4.16, or 32 micromoles/L zinc respectively. Nuclear p53 levels were nearly 100% and 40% higher in ZD0.2 and ZD0.4 cells, respectively than in ZN cells. In contrast, p53 mRNA abundance was depressed 60% in ZD0.2 cells and increased 40% in ZD0.4 cells as compared with ZN cells. Mdm2 protein, which modulates p53 nuclear export and degradation, was more than twofold higher in the nucleus of ZD0.2 and ZD0.4 cells than in ZN cells. This may have resulted from the observed increase in c-Abl binding to Mdm2, which is known to enhance Mdm2 nuclear accumulation. Nevertheless, the actual amount of Mdm2 bound to p53 was depressed and that to Mdmx was increased in ZD0.2 and ZD0.4 cells than in ZN cells. These changes are known to interfere with Mdm2-dependent p53 nuclear export that results in p53 nuclear accumulation. In zinc deficiency, the reduced binding of Mdm2 to p53 may have resulted from the observed enhanced phosphorylation of p53 at serine 15 and 392, and of Mdm2 at a tyrosine residue.