Potentially, under these studied conditions, the levels of Mt-I and Mt-II are sufficient to chelate the elevated copper. Therefore, it would be of interest to complementary deplete Mt-I and Mt-II in our hepatic-specific Commd1 knockout mice and assess the protective role of Mt-I and Mt-II in copper toxicity in the absence of Commd1. In contrast to Commd1Dhep mice fed a high copper diet, which display copper concentrations of approximately 340 mg/g of dlw, CT-affected dogs with moderate to severe liver pathology show significantly more hepatic copper, often in excess of 1,000 mg/g of dlw. The reason for the interspecies differences is currently unknown and further studies are required. Of particular interest in this would be defining the degree of redundancy between the members of the Commd protein family in murine copper homeostasis, as in addition to COMMD1, COMMD2, 8 and 10 have also the ability to interact with ATP7B. Importantly, these interactions are independent of COMMD1 expression. Together, our data conclusively shows that COMMD1 plays a significant role in copper homeostasis and demonstrates that hepatic copper accumulation due to loss of Commd1 is dependent on excessive dietary copper intake. Given that elevated asymptomatic hepatic copper in Atp7b deficient mice has a significant effect on different metabolic pathways, such as lipid metabolism, it would be of interest to investigate whether dietinduced copper accumulation in Commd1Dhep mice also affects these pathways. We believe that our Commd1Dhep mice represent a valuable and interesting model for further elucidating the molecular mechanism controlling hepatic copper homeostasis and to understand the role of excess copper in various metabolic pathways. The output of a gene is determined by its rate of transcription, the post-transcriptional processing and stability of the mRNA, its translation rate and the post-translational control of protein activity and stability. Despite the fact that cellular mRNAs share a common set of important structural features like the 59-cap and poly-A tail, large variations in mRNA half-life are SU5416 204005-46-9 observed, e.g. spanning from less than one hour to.24 h in mouse ES cell lines. The degradation rate of mRNAs is determined by specific regulatory sequences, for which the family of AU-rich elements is a well studied example. They were discovered in the 39- untranslated region of unstable mRNAs coding for cytokines. When transposed into an otherwise stable mRNA, AREs cause the mRNA to be deadenylated and degraded rapidly. Based on sequence differences and deadenylation kinetics, several classes of AREs have been defined. Presumably, different classes of AREs recruit distinct sets of RNA-binding proteins, resulting in differential regulation. For example, Tristetraprolin binds to class II AREs that typically occur in cytokine mRNAs and causes rapid ARE-mediated mRNA decay. The destabilizing activity of TTP, however, is not constitutive: It can be temporally masked through phosphorylation of TTP by the mitogen-activated protein kinase-activated protein kinase 2. This additional level of control helps to generate a transient peak of cytokine expression.