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zsh v10.3.zip..mlp v10.3.5.zip.mlp.Due to the significance ofmetallothioneins in stress responses, and their role in humandisease, there is an increasing interest in their mechanisms ofaction and gene regulation. Three related promoters have beenfound to influence the expression of Metallothioneins-1 and -2.
While the two proximal promoters mediate responses to nickel andcadmium, the third, located 30 kb away, is specific for copperresponses. I propose to continue the analysis of the copperinducible promoter. I will define the response elements by deletionand mutational analysis, and define the region that confers
constitutive expression. This should help in elucidating thefunction of the metal-responsive elements and hopefully identify
additional transcription factors that interact with this region.
Second, I will investigate the role of a specific homeobox genethat is expressed in response to copper and binds specifically tothe region that mediates the copper response. This gene isimportant for mouse development and mutation of its coding
region causes abnormalities in the nervous system and skeleton.
Preliminary data indicates that the homeobox protein is a zincfinger containing DNA binding protein and is a paralogue of Pax2,
which has been implicated in kidney development. I will
characterize this gene and its role in development by defining its

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expression pattern and performing in situ hybridization with wholemount embryos as well as transgenic mice. Lastly, I will initiate
studies on the role of metallothioneins in copper homeostasis.
Since a tumor microenvironment has been found to exhibit
increased expression of copper-inducible metallothioneins, I willassess the importance of these genes in tumorigenesis. I will
determine whether metallothioneins participate in theenhancement of tumorigenicity by the addition of copper, and willassess the effect of these genes on tumor cell growth in nude
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