Analysis of a novel mechanism for the post-transcriptional regulation of protein kinase Hipk2 expression

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The project described here deals with novel findings on the function of the protein kinase Hipk2 and the tumor suppressor Pdcd4 in the post-transcriptional regulation of Hipk2 expression. Our preliminary work has shown that Hipk2 and Pdcd4 are involved in the antagonistic regulation of the translation of Hipk2 mRNA by a novel mechanism. We have found that the translation of Hipk2 mRNA is stimulated in an autoregulatory manner by Hipk2 itself and that Pdcd4 disrupts this autoregulatory mechanism, thereby inhibiting Hipk2 expression. This demonstrates for the first time that Hipk2 expression is not only controlled by proteasomal degradation, as presently assumed, but that it can also be regulated by its synthesis. This points to an additional level of regulation of Hipk2, which has not been investgated so far. Furthermore, our preliminary work has shown that Pdcd4 modulates the synthesis of Hipk2 and thereby might influence Hipk2-regulated processes. By using Pdcd4 mutants we have also found that the inhibition of Hipk2 mRNA translation by Pdcd4 must occur by a novel mechanism that is distinct from the previously described mechanisms of translation suppression by Pdcd4. The aim of this project is to study the antagonistic effects of Hipk2 and Pdcd4 on the translation of Hipk2 mRNA in order to understand the molecular basis into these novel roles of both proteins in the regulation of translation. The characterization of these mechanisms will lead to novel insight into the function of these highly conserved proteins in normal and in tumor cells.