Exposure to heavy metal ions can result in acute toxicity. In addition, exposure to certain heavy metals such as Cr, Ni, As and Cd can lead to carcinogenesis. Some protection against the toxic and carcinogenic effects of heavy metal ions is provided by the metallothioneins (MT), which are low molecular weight, cystein rich, heavy metal binding proteins. We will continue our studies on the regulation of MT gene expression by toxic and essential heavy metals, such as Cd and Zn. We will characterize the proteins encoded by three different cDNAs that were isolated based on their ability to activate expression of genes that contain metal response elements (MREs) in yeast. DNA binding as says will be used to study the interaction of these proteins with the MRE and determine which one of them is the sought-after metal response factor (MRF). The mechanism by which heavy metal ions control the activity of the MRF will be investigated using biochemical and reversed genetic approaches. In addition, we plan to initiate new research on the mechanisms by which heavy metals exert their carcinogenic activities. At the present time carcinogenicity by heavy metal ions is not well understood. As there is little evidence that carcinogenic heavy metals such as As or Cd act as tumor initiators via a standard genotoxic mechanism, we propose that they are more likely to act as tumor promoters by causing oxidative stress. Since tumor promotion by phorbol esters is known to be associated with increased expression of the jun and fos protooncogenes, we will investigate the induction of these genes in response to heavy metal ions. A likely induction mechanism could be initiated with either the inhibition of tyrosine phosphatases or with the activation of tyrosine kinases by heavy metal induced oxidative stress. Activation of tyrosine kinases triggers a signalling cascade that results in the stimulation of serine/threonine specific protein kinases including a protein kinase that phosphorylates and potentiates the activity of the cJun protein, leading to auto-stimulatory induction of c-jun gene expression. Deregulated cJun expression is known to cause neoplastic transformation. We will investigate whether heavy metal ions activate this pathway and whether this activation can be reversed by increasing the intracellular level of reduced glutathione. These studies should provide us with a molecular basis for understanding how certain heavy metal ions can act as tumor promoters and thereby exert their carcinogenic activity. These studies are expected to shed light on a scantly studied area of heavy metal toxicology.
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