Ostareck-Lederer Antje, Ostareck Dirk H, Cans Christophe, Neubauer Gitte, Bomsztyk Karol, Superti-Furga Giulio, Hentze Matthias W
European Molecular Biology Laboratory, Heidelberg, Germany.
Mol Cell Biol. 2002 Jul;22(13):4535-43. doi: 10.1128/MCB.22.13.4535-4543.2002.
hnRNPK and hnRNP E1/E2 mediate translational silencing of cellular and viral mRNAs in a differentiation-dependent way by binding to specific regulatory sequences. The translation of 15-lipoxygenase (LOX) mRNA in erythroid precursor cells and of the L2 mRNA of human papilloma virus type 16 (HPV-16) in squamous epithelial cells is silenced when either of these cells is immature and is activated in maturing cells by unknown mechanisms. Here we address the question of how the silenced mRNA can be translationally activated. We show that hnRNP K and the c-Src kinase specifically interact with each other, leading to c-Src activation and tyrosine phosphorylation of hnRNP K in vivo and in vitro. c-Src-mediated phosphorylation reversibly inhibits the binding of hnRNP K to the differentiation control element (DICE) of the LOX mRNA 3' untranslated region in vitro and specifically derepresses the translation of DICE-bearing mRNAs in vivo. Our results establish a novel role of c-Src kinase in translational gene regulation and reveal a mechanism by which silenced mRNAs can be translationally activated.
hnRNPK和hnRNP E1/E2通过与特定调控序列结合，以分化依赖的方式介导细胞和病毒mRNA的翻译沉默。当红系前体细胞中的15-脂氧合酶（LOX）mRNA以及鳞状上皮细胞中人乳头瘤病毒16型（HPV-16）的L2 mRNA在细胞未成熟时会发生翻译沉默，而在成熟细胞中通过未知机制被激活。在此，我们探讨沉默的mRNA如何被翻译激活这一问题。我们发现hnRNP K与c-Src激酶在体内和体外均特异性相互作用，导致c-Src激活以及hnRNP K的酪氨酸磷酸化。c-Src介导的磷酸化在体外可逆地抑制hnRNP K与LOX mRNA 3'非翻译区的分化控制元件（DICE）的结合，并在体内特异性解除对携带DICE的mRNA的翻译抑制。我们的结果确立了c-Src激酶在翻译基因调控中的新作用，并揭示了沉默mRNA可被翻译激活的机制。
