Zinc is an essential nutrient for human health and has anti-oxidative stress and anti-inflammatory functions. The association between zinc deficiency and the development of cardiovascular diseases (CVDs) has been supported by numerous studies. Supplementing zinc can reduce the risk of atherosclerosis and protect against myocardial infarction and ischemia/reperfusion injury. In this review we summarize the evidence in the literature, to consolidate the current knowledge on the dysregulation of zinc homeostasis in CVDs, and to explore the significant roles of the zinc homeostasis-regulatory proteins in cardiac physiology and pathophysiology. Moreover, this review also deliberates on the potential diagnostic and prognostic implications of zinc/zinc homeostasis-associated molecules (ZIP, ZnT, and MTs) in CVDs.

Disruption of the function of tumor suppressor proteins occasionally can be dependent on their subcellular localization. In about 40% of the breast cancer tissues, p53 is found in the cytoplasm as opposed to the nucleus, where it resides in normal breast cells. This means that the regulation of subcellular location of p53 is an important mechanism in controlling its function. The transport factors required for the nuclear export of p53 and the mechanisms of their nuclear export have been extensively characterized. However, little is known about the mechanism of nuclear import of p53. p53 contains putative nuclear localization signals (NLSs) which would interact with a nuclear transport factor, importin ␣. In this report we demonstrate that importin ␣ binds to NLSI in p53 and mediates the nuclear import of p53. Reverse transcriptase-polymerase chain reaction and sequencing analyses showed that a truncated importin ␣ deleted the region encoding the putative NLS-binding domain of p53, suggesting that it could not bind to NLSs of p53 proteins. Binding of importin ␣ to p53 was confirmed by using yeast two-hybrid assay. When expressed in CHO-K1 cells, the truncated importin ␣ predominantly localized to the cytoplasm. In truncated importin ␣ expressing cells, p53 preferentially localized to cytoplasmic sites as well. A significant increase in the p21 waf1/cip1 mRNA level and induction of apoptosis were also observed in importin ␣ overexpressing cells. These results strongly suggest that importin ␣ functions as a component of the NLS receptor for p53 and mediates nuclear import of p53.p53 is a tumor suppressor gene and various p53 gene mutations are found in over 50% of all human cancers (1). Although inactivation of tumor suppressor proteins is generally thought to originate in their genetic mutations, disruption of their function can occasionally be independent of such mutations. Moll et al. (2) have reported that about 37% out of 27 samples of breast cancer tissues showed cytoplasmic localization of wild-type p53, resulting in inhibition of normal p53 function (2). Nuclear exclusion of wild-type p53 has also been reported in neuroblastoma and colon carcinoma cells (3, 4). In another study, wild-type p53 was located in the cytoplasm of human cervical carcinoma cell lines with integrated human papillomavirus-18 or -16 (5). In colon carcinoma, cytoplasmic accumulation of p53 correlates with unfavorable prognosis (4). These data indicate that the regulation of p53 subcellular location is an important mechanism in controlling p53 function.In eukaryotic cells, the nucleus is separated from the cytoplasm by the nuclear envelope. This spatial segregation requires a nuclear transport system to correctly import or export nuclear components at the proper time. The prototype of the nuclear transport signal is the classical nuclear localization signal (NLS), 1 and nuclear import of proteins bearing an NLS is dependent on two cellular factors termed importin ␣ and importin ␤ (6 -11). The initial cytoplasmic event in NLS-dependent...

Zinc-responsive transcription factors are found in all kingdoms of life and include the transcriptional activators ZntR, SczA, Zap1, bZip19, bZip23, and MTF-1, and transcriptional repressors Zur, AdcR, Loz1, and SmtB. These factors have two defining features; their activity is regulated by zinc and they all play a central role in zinc homeostasis by controlling the expression of genes that directly affect zinc levels or its availability. This review summarizes what is known about the mechanisms by which each of these factors sense changes in intracellular zinc levels and how they control zinc homeostasis through target gene regulation. Other factors that influence zinc ion sensing are also discussed.

Zinc, an essential micronutrient, has a cancer preventive role. Zinc deficiency has been shown to contribute to the progression of esophageal cancer. Orai1, a store-operated Ca entry (SOCE) channel, was previously reported to be highly expressed in tumor tissues removed from patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis, and elevation of its expression contributes to both hyperactive intracellular Ca oscillations and fast cell proliferation in human ESCC cells. However, the molecular basis of cancer preventive functions of zinc and its association with Orai1-mediated cell proliferation remains unknown. The present study shows that zinc supplementation significantly inhibits proliferation of ESCC cell lines and that the effect of zinc is reversible with ,,,-tetrakis (2-pyridylmethyl) ethylenediamine, a specific Zn chelator, whereas nontumorigenic esophageal epithelial cells are significantly less sensitive to zinc treatment. Fluorescence live cell imaging revealed that extracellular Zn exerted rapid inhibitory effects on Orai1-mediated SOCE and on intracellular Ca oscillations in the ESCC cells. Knockdown of Orai1 or expression of Orai1 mutants with compromised zinc binding significantly diminished sensitivity of the cancer cells to zinc treatment in both SOCE and cell proliferation analyses. These data suggest that zinc may inhibit cell proliferation of esophageal cancer cells through Orai1-mediated intracellular Ca oscillations and reveal a possible molecular basis for zinc-induced cancer prevention and Orai1-SOCE signaling pathway in cancer cells.-Choi, S., Cui, C., Luo, Y., Kim, S.-H., Ko, J.-K., Huo, X., Ma, J., Fu, L.-W., Souza, R. F., Korichneva, I., Pan, Z. Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1.