3′UTR elements inhibit Ras-induced C/EBPβ post-translational activation and senescence in tumour cells

Abstract

C/EBPβ is an auto‐repressed protein that becomes post‐translationally activated by Ras‐MEK‐ERK signalling. C/EBPβ 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/EBPβ activation by H‐RasV12 is suppressed in immortalized/transformed cells, but not in primary cells, by its 3′ untranslated region (3′UTR). 3′UTR sequences inhibited Ras‐induced cytostatic activity of C/EBPβ, DNA binding, transactivation, phosphorylation, and homodimerization, without significantly affecting protein expression. The 3′UTR suppressed induction of senescence‐associated C/EBPβ target genes, while promoting expression of genes linked to cancers and TGFβ 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/EBPβ translation controls de‐repression by Ras signalling. Notably, 3′UTR inhibition and Cebpb mRNA compartmentalization were absent in primary fibroblasts, allowing Ras‐induced C/EBPβ activation and OIS to proceed. Our findings reveal a novel mechanism whereby non‐coding mRNA sequences selectively regulate C/EBPβ activity and suppress its anti‐oncogenic functions.

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

“…6a), indicating that the TSP-1 promoter is not a direct target of the chimera. TSP-1 is a target of C/EBPb, 21 a master regulator of adipogenesis and preferential dimerization partner of DDIT3. A significant enrichment in TSP-1 promoter associated to C/EBPb was detected in untreated tumors but not following trabectedin treatment (Fig.…”

C/EBPγ Suppresses Senescence and Inflammatory Gene Expression by Heterodimerizing with C/EBPβ

“…NF-B and C/EBP␤ are inducible transcription factors that regulate SASP gene transcription (6)(7)(8)(9)(10). Genetic studies and RNA interference (RNAi) experiments have also demonstrated that C/EBP␤ is required for OIS in human and murine fibroblasts (7,11).…”

C/EBPβ: lost beyond translation

“…In this issue of The EMBO Journal, Peter Johnson and colleagues reveal yet another facet of C/EBPb regulation, and it is a most original one (Basu et al, 2011). The investigators asked whether the 3 0 UTR of the C/EBPb transcript contributes to the downregulation of its resultant protein product by oncogenic RAS, an observation they made earlier (Sebastian and Johnson, 2009).…”

“…Correspondingly, whereas active C/EBPb lacking the 3 0 UTR stimulated the senescence-associated secretome as expected (Kuilman and Peeper, 2009), the full-length messenger failed to do so. Lastly, Basu et al (2011) show that this phenomenon is specific for immortalized and oncogenically transformed cells, as primary cells with a reduced cytoplasmic HuR pool apparently abrogate the negative effects of the 3 0 UTR, allowing for OIS to occur.…”

“…In this issue of The EMBO Journal, Basu et al (2011) describe a new function for AREs, in the context of the C/EBPb transcription factor. Specifically, they show that the C/EBPb ARE is responsible for sequestering the corresponding protein from subcellular compartments in which kinases reside to derepress C/EBPb.…”