3'UTR elements inhibit Ras-induced C/EBPß post-translational activation and senescence in tumour cells.
EMBO J
; 30(18): 3714-28, 2011 Jul 29.
Article
en En
| MEDLINE
| ID: mdl-21804532
ABSTRACT
C/EBPß is an auto-repressed protein that becomes post-translationally activated by Ras-MEK-ERK signalling. C/EBPß 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/EBPß 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/EBPß, DNA binding, transactivation, phosphorylation, and homodimerization, without significantly affecting protein expression. The 3'UTR suppressed induction of senescence-associated C/EBPß target genes, while promoting expression of genes linked to cancers and TGFß 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/EBPß translation controls de-repression by Ras signalling. Notably, 3'UTR inhibition and Cebpb mRNA compartmentalization were absent in primary fibroblasts, allowing Ras-induced C/EBPß activation and OIS to proceed. Our findings reveal a novel mechanism whereby non-coding mRNA sequences selectively regulate C/EBPß activity and suppress its anti-oncogenic functions.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Envejecimiento
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Proteína Oncogénica p21(ras)
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Regulación de la Expresión Génica
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Regiones no Traducidas 3'
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Proteína beta Potenciadora de Unión a CCAAT
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
EMBO J
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos