Ohnheiser Johanna, Ferlemann Eva, Haas Astrid, Müller Jan P, Werwein Eugen, Fehler Olesja, Biyanee Abhiruchi, Klempnauer Karl-Heinz
Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany; Graduate School of Chemistry (GSC-MS), Westfälische-Wilhelms-Universität Münster, Germany.
Biochim Biophys Acta. 2015 Jul;1853(7):1564-73. doi: 10.1016/j.bbamcr.2015.03.008. Epub 2015 Mar 25.
The tumor suppressor protein programmed cell death 4 (Pdcd4) is a highly conserved RNA-binding protein that inhibits the translation of specific mRNAs. Here, we have identified the homeobox-interacting protein kinase-2 (Hipk2) mRNA as a novel translational target of Pdcd4. Unlike most other protein kinases Hipk2 is constitutively active after being synthesized by the ribosome and its expression and activity are thought to be mainly controlled by modulation of the half-life of the kinase. Our work provides the first evidence that Hipk2 expression is also controlled on the level of translation. We show that Hipk2 stimulates the translation of its own mRNA and that Pdcd4 suppresses the translation of Hipk2 mRNA by interfering with this auto-regulatory feedback mechanism. We also show that the translation of the related kinase Hipk1 is controlled by a similar feedback loop and that Hipk2 also stimulates the translation of Hipk1 mRNA. Taken together, our work describes a novel mechanism of translational suppression by Pdcd4 and shows for the first time that Hipk2 controls its own synthesis by an auto-regulatory feedback mechanism. Furthermore, the effect of Hipk2 on the translation of Hipk1 RNA suggests that Hipk2 and Pdcd4 can act in similar manner to control the translation of other mRNAs.
肿瘤抑制蛋白程序性细胞死亡4（Pdcd4）是一种高度保守的RNA结合蛋白，可抑制特定mRNA的翻译。在此，我们已确定同源框相互作用蛋白激酶2（Hipk2）mRNA是Pdcd4的一个新的翻译靶点。与大多数其他蛋白激酶不同，Hipk2在由核糖体合成后即组成性激活，其表达和活性被认为主要通过调节激酶的半衰期来控制。我们的工作提供了首个证据，表明Hipk2的表达在翻译水平上也受到控制。我们发现Hipk2刺激其自身mRNA的翻译，而Pdcd4通过干扰这种自调节反馈机制来抑制Hipk2 mRNA的翻译。我们还表明，相关激酶Hipk1的翻译受类似的反馈环控制，并且Hipk2也刺激Hipk1 mRNA的翻译。综上所述，我们的工作描述了一种由Pdcd4介导的翻译抑制新机制，并首次表明Hipk2通过自调节反馈机制控制其自身的合成。此外，Hipk2对Hipk1 RNA翻译的影响表明，Hipk2和Pdcd4可能以类似方式作用，以控制其他mRNA的翻译。
