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

这里描述的项目涉及新的发现的功能的蛋白激酶Hipk2和肿瘤抑制因子Pdcd4的转录后调节Hipk2的表达。我们的初步工作表明，Hipk2和Pdcd4通过一种新的机制参与了Hipk2 mRNA翻译的拮抗调节。我们已经发现，Hipk2 mRNA的翻译是由Hipk2本身以自动调节的方式刺激的，Pdcd4破坏了这种自动调节机制，从而抑制Hipk2的表达。这第一次表明，Hipk2的表达不仅是由蛋白酶体降解控制，目前假设，但它也可以通过其合成调节。这表明了Hipk2的另一个调节水平，迄今为止还没有研究过。此外，我们的初步工作表明，Pdcd4调节Hipk2的合成，从而可能影响Hipk2调节的过程。通过使用Pdcd4突变体，我们还发现Pdcd4对Hipk2 mRNA翻译的抑制必须通过一种新的机制发生，该机制不同于先前描述的Pdcd4抑制翻译的机制。本项目的目的是研究Hipk2和Pdcd4对Hipk2 mRNA翻译的拮抗作用，以了解这两种蛋白在翻译调控中的新作用的分子基础。这些机制的表征将导致新的洞察这些高度保守的蛋白质在正常和肿瘤细胞中的功能。

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.