Document Detail

HuR-mediated control of CEBP{beta} mRNA stability and translation in ALK-positive Anaplastic Large Cell Lymphoma.
MedLine Citation:
PMID:  21343335     Owner:  NLM     Status:  Publisher    
The CCAAT/enhancer-binding protein B (CEBPB) plays a major role in the pathogenesis of Anaplastic Large Cell Lymphomas (ALCLs) that express the NPM-ALK tyrosine kinase (ALK+). Although ALK-mediated CEBPB transcriptional activation has been reported, C/EBPB mRNA possesses U- and AU-rich domains in its 3' untranslated region that might be privileged targets for post-transcriptional control in ALK+ ALCLs. The purpose of this study was to explore this possibility. Using human ALCL-derived cells and a murine model of ALK-transformed cells, we have shown that the AU-binding protein HuR binds to the 3'-UTR of C/EBPB mRNA, as previously reported in adipocytes, and that NPM-ALK enhances this interaction. Interaction between HuR and CEBPB mRNA impacts on C/EBPB gene expression at both the mRNA and protein levels. Indeed, C/EBPB 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+ cells. HuR/polysomes association diminishes when NPM-ALK activity is inhibited, and is accompanied by a concomitant decrease of C/EBPB mRNA translation. Finally, we have shown that HuR and NPM-ALK co-localised in cytoplasmic granules and that HuR is phosphroylated on tyrosine residue in ALK+ ALCL cells. Our study thus demonstrates that C/EBPB is indeed regulated at the post-transcriptional level by HuR in ALK+ 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.
Julie Bergalet; Mohamad Fawal; Céline Lopez; Cécile Desjobert; Laurence Lamant; Georges Delsol; Dominique Morello; Estelle Espinos
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-2-22
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  -     ISSN:  1557-3125     ISO Abbreviation:  -     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-2-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Signalisation et Innovation Thérapeutique, INSERM U563.
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