Unknown,Transcriptomics,Genomics,Proteomics

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Epigenetic activation of a subset of mRNAs identified using polyribosome microarray analysis

ABSTRACT: Background: Translation deregulation is an important mechanism that causes aberrant cell growth, proliferation and survival. eIF4E, the mRNA 5 prime capâ??binding protein, plays a major role in translational control. To understand how eIF4E affects cellular proliferation and cell survival, we identified mRNA targets that are translationally responsive to eIF4E. Methodology/ principal findings: Microarray analysis of polysomal mRNA from an eIF4E-inducible NIH 3T3 cell line was performed. Induction of eIF4E expression resulted in increased translation of a defined set of mRNAs; many of the mRNAs are novel targets, including those that encode large- and small-subunit ribosomal proteins and cell growthâ??related factors. eIF4E overexpression also led to augmented translation of mRNAs encoding anti-apoptotic proteins, which conferred resistance to endoplasmic reticulumâ??mediated apoptosis. Conclusions/ significance: Our results shed new light on the mechanisms by which eIF4E prevents apoptosis and transforms cells. Downregulation of eIF4E and its downstream targets is a therapeutic option for the development of novel anti-cancer drugs. Keywords: time course Comparison of total and polysomal RNA upon eIF4E iinduction in NIH3T3/parental and NIH3T3/eIF4E cells Each of the following pairs were generated from one hybridization: GSM153931 GSM153932 GSM153933 GSM153934 GSM153935 GSM153936 GSM153937 GSM153938 GSM153939 GSM153940 GSM153941 GSM153942 GSM153943 GSM153944 GSM153945 GSM153946 GSM153947 GSM153948 GSM153949 GSM153950 GSM153951 GSM153952 GSM153953 GSM153954 GSM153955 GSM153956 GSM153957 GSM153958 GSM153959 GSM153960 GSM153961 GSM153962

ORGANISM(S): Mus musculus

SUBMITTER: Ola Larsson

PROVIDER: E-GEOD-6639 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation.

Mamane Yaël Y Petroulakis Emmanuel E Martineau Yvan Y Sato Taka-Aki TA Larsson Ola O Rajasekhar Vinagolu K VK Sonenberg Nahum N

PloS one 20070221 2

<h4>Background</h4>Translation deregulation is an important mechanism that causes aberrant cell growth, proliferation and survival. eIF4E, the mRNA 5' cap-binding protein, plays a major role in translational control. To understand how eIF4E affects cell proliferation and survival, we studied mRNA targets that are translationally responsive to eIF4E.<h4>Methodology/principal findings</h4>Microarray analysis of polysomal mRNA from an eIF4E-inducible NIH 3T3 cell line was performed. Inducible expre ...[more]

PMID: 17311107

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Project description:Translation initiation factor eIF4E is overexpressed early in breast cancers in association with disease progression and reduced survival. Much remains to be understood regarding the role of eIF4E in human cancer. Using immortalized human breast epithelial cells, we report that elevated expression of elF4E translationally activates the TGFβ pathway, promoting cell invasion, loss of cell polarity, increased cell survival and other hallmarks of early neoplasia. Overexpression of eIF4E is shown to facilitate selective translation of integrin β1 mRNA, which drives the translationally controlled assembly of a TGFβ receptor signaling complex containing α3β1 integrins, β-catenin, TGFβ receptor I, E-cadherin and phosphorylated Smads2/3. This receptor complex acutely sensitizes non-malignant breast epithelial cells to activation by typically sub-stimulatory levels of activated TGFβ. TGFβ can promote cellular differentiation or invasion and transformation. As a translational coactivator of TGFβ, eIF4E confers selective mRNA translation, reprogramming non-malignant cells to an invasive phenotype by reducing the set-point for stimulation by activated TGFβ. Overexpression of eIF4E may be a pro-invasive facilitator of TGFβ activity. MCF10A cells were subjected to consitutive silencing with a non-silencing control shRNA or an shRNA to eIF4E. Total RNA, light polysomal RNA (2-3 ribosome fraction) and heavy polysomal RNA (greater than or equal to 4 ribosome fraction) were purified and used for hybridization to Affymetrix 133 2.0 Plus arrays. Data analysis was conducted using MicroArray Suite Software from Affymetrix. To remove probe sets with insignificant differences between perfect match and mismatch data, which creates a more robust data set of greater clarity without a high level of background noise, discrimination values for each probe pair were calculated for low intensity ratios using Wilcoxon signed rank test to assess significance and data re-assigned as either changed or unchanged mRNAs. Data sets were compared using Expressionist Suite software. Significance of mRNAs were assessed using fold changes and the FDRs estimated based on t-tests.

Dataset Information

Epigenetic activation of a subset of mRNAs identified using polyribosome microarray analysis

Publications

Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation.

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