Data from HuR-Mediated Control of <i>C/EBPβ</i> mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

Abstract

&lt;div&gt;Abstract&lt;p&gt;The CCAAT/enhancer-binding protein &lt;i&gt;β&lt;/i&gt; (C/EBPβ) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK&lt;sup&gt;+&lt;/sup&gt;). Although ALK-mediated &lt;i&gt;C/EBPβ&lt;/i&gt; transcriptional activation has been reported, &lt;i&gt;C/EBPβ&lt;/i&gt; mRNA possesses U- and AU-rich domains in its 3′-untranslated region (3′-UTR) that might be privileged targets for posttranscriptional control in ALK&lt;sup&gt;+&lt;/sup&gt; ALCLs. The purpose of this study was to explore this possibility. By using human ALCL-derived cells and a murine model of ALK-transformed cells, we show that the AU-binding protein HuR binds to the 3′-UTR of &lt;i&gt;C/EBPβ&lt;/i&gt; mRNA, as previously reported in adipocytes, and that NPM-ALK enhances this interaction. Interaction between HuR and &lt;i&gt;C/EBPβ&lt;/i&gt; mRNA impacts on &lt;i&gt;C/EBPβ&lt;/i&gt; gene expression at both the mRNA and protein levels. Indeed, &lt;i&gt;C/EBPβ&lt;/i&gt; mRNA stability following HuR silencing is reduced and reaches the value observed in ALK-inactivated cells. Remarkably, HuR expression is not modified by NPM-ALK, but its association with actively translating polysomes is dramatically increased in ALK&lt;sup&gt;+&lt;/sup&gt; cells. HuR/polysomes association diminishes when NPM-ALK activity is inhibited and is accompanied by a concomitant decrease of &lt;i&gt;C/EBPβ&lt;/i&gt; mRNA translation. Finally, we show that HuR and NPM-ALK colocalized in cytoplasmic granules and HuR is phosphroylated on tyrosine residues in ALK&lt;sup&gt;+&lt;/sup&gt; ALCL cells. Our study thus demonstrates that &lt;i&gt;C/EBPβ&lt;/i&gt; is indeed regulated at the posttranscriptional level by HuR in ALK&lt;sup&gt;+&lt;/sup&gt; cells, leading us to propose that part of NPM-ALK oncogenic properties relies on its ability to modify HuR properties in the cytoplasm and hence to alter expression of key actors of transformation. &lt;i&gt;Mol Cancer Res; 9(4); 485–96. ©2011 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;