title: 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-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.
authors.affiliation: Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute-Frederick, NIH, MD, USA.
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Basu
authors.forename: Radek
authors.initials: R
authors.lastname: Malik
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Huggins
authors.forename: Sook
authors.initials: S
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: Sebastian
authors.forename: Krisada
authors.initials: K
authors.lastname: Sakchaisri
authors.forename: Octavio A
authors.initials: OA
authors.lastname: Quiñones
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
mesh_terms: D020413:3' Untranslated Regions; D000375:Aging; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D012333:RNA, Messenger; D015689:Oncogene Protein p21(ras)