3 ' UTR elements inhibit Ras-induced C/EBP beta post-translational activation and senescence in tumour cells

[摘要]：C/EBP beta is an auto-repressed protein that becomes post-translationally activated by Ras-MEK-ERK signalling. C/EBP beta is required for oncogene-induced senescence (OIS) of primary fibroblasts, but also displays pro-oncogenic functions in many tumour cells. Here, we show that C/EBP beta activation by H-Ras(V12) is suppressed in immortalized/transformed cells, but not in primary cells, by its 30 untranslated region (3'UTR). 3'UTR sequences inhibited Ras-induced cytostatic activity of C/EBP beta, DNA binding, transactivation, phosphorylation, and homodimerization, without significantly affecting protein expression. The 3'UTR suppressed induction of senescence-associated C/EBP beta target genes, while promoting expression of genes linked to cancers and TGF beta signalling. An AU-rich element (ARE) and its cognate RNA-binding protein, HuR, were required for 3'UTR inhibition. These components also excluded the Cebpb mRNA from a perinuclear cytoplasmic region that contains activated ERK1/2, indicating that the site of C/EBP beta translation controls de-repression by Ras signalling. Notably, 3'UTR inhibition and Cebpb mRNA compartmentalization were absent in primary fibroblasts, allowing Ras-induced C/EBP beta activation and OIS to proceed. Our findings reveal a novel mechanism whereby non-coding mRNA sequences selectively regulate C/EBP beta activity and suppress its anti-oncogenic functions. The EMBO Journal (2011) 30, 3714-3728. doi: 10.1038/emboj.2011.250; Published online 29 July 2011

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