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Influence of C/EBPβ 3'UTR on RasV12 induced gene expression

ABSTRACT: C/EBPb is an auto-repressed protein that becomes posttranslationally activated by Ras-MEK-ERK signalling. C/EBPb 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/EBPb activation by H-RasV12 is suppressed in immortalized/transformed cells, but not in primary cells, by its 30 untranslated region (30UTR). 30UTR sequences inhibited Ras-induced cytostatic activity of C/EBPb, DNA binding, transactivation, phosphorylation, and homodimerization, without significantly affecting protein expression. The 30UTR suppressed induction of senescence-associated C/EBPb target genes, while promoting expression of genes linked to cancers and TGFb signalling. An AU-rich element (ARE) and its cognate RNA-binding protein, HuR, were required for 30UTR inhibition. These components also excluded the Cebpb mRNA from a perinuclear cytoplasmic region that contains activated ERK1/2, indicating that the site of C/EBPb translation controls de-repression by Ras signalling. Notably, 30UTR inhibition and Cebpb mRNA compartmentalization were absent in primary fibroblasts, allowing Ras-induced C/EBPb activation and OIS to proceed. Our findings reveal a novel mechanism whereby non-coding mRNA sequences selectively regulate C/EBPb activity and suppress its anti-oncogenic functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE30834 | GEO | 2011/07/23

SECONDARY ACCESSION(S): PRJNA144175

REPOSITORIES: GEO

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Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces Ã¢Â?Â?SASP-likeÃ¢Â?Â? inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study examines the genome-wide distribution of gH2A.x and H3K4me3 by chIP-seq, using input and whole histone subunit H3 (respectively) as controls for local sonication efficiency bias. Each of the four chIPs has a single replicate each in (i) IMR90 fibroblasts transfected with a scramble control vector, (ii) the same cells subject to oncogene-induced senescence by stimulation of H-Ras V12, and (iii) in OIS cells with a shRNA targeting MLL1. Additionally, gH2A.x and input were sequenced with another replicate in control and OIS cells (both scramble control).

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Influence of C/EBPβ 3'UTR on RasV12 induced gene expression

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