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3′UTR elements inhibit Ras‐induced C/EBPβ post‐translational activation and senescence in tumour cells
Author(s) -
Basu Sandip K,
Malik Radek,
Huggins Christopher J,
Lee Sook,
Sebastian Thomas,
Sakchaisri Krisada,
Quiñones Octavio A,
Alvord W Gregory,
Johnson Peter F
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.250
Subject(s) - biology , untranslated region , transactivation , three prime untranslated region , messenger rna , microbiology and biotechnology , translation (biology) , gene expression , gene , genetics
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‐Ras V12 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.