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

蛋白激酶 Hipk2 表达转录后调控新机制分析

• 批准号: 281666681
• 负责人: Professor Dr. Karl-Heinz Klempnauer
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/281666681?language=en
• 关键词: Analysis; novel; mechanism; post; transcriptional

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.

这里描述的项目涉及蛋白激酶Hipk2和肿瘤抑制因子Pdcd4在Hipk2表达转录后调控中的功能的新发现。我们的初步工作表明，Hipk2和Pdcd4通过一种新机制参与了Hipk2 mRNA翻译的拮抗调节。我们发现Hipk2 mRNA的翻译是由Hipk2自身以一种自我调节的方式刺激的，而Pdcd4破坏了这种自我调节机制，从而抑制了Hipk2的表达。这首次证明Hipk2的表达不仅受到蛋白酶体降解的控制，而且还可以通过其合成来调节。这指出了Hipk2的另一个调控水平，迄今为止尚未对其进行研究。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调控的过程。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不同于先前描述的Pdcd4翻译抑制机制的新机制发生。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调节翻译中的新作用的分子基础。这些机制的表征将导致对这些高度保守蛋白在正常和肿瘤细胞中的功能的新见解。