Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide analysis of RNAs translationally regulated upon BRCA1 depletion in human mammary epithelial cells

ABSTRACT: Loss of function of the tumor suppressor BRCA1 (Breast Cancer 1) protein is responsible for numerous familial and sporadic breast cancers. We previously identified PABP1 as a novel BRCA1 partner and showed that BRCA1 modulates translation through its interaction with PABP1. We showed that the global translation was diminished in BRCA1-depleted cells and increased in BRCA1-overexpressing cells. Our findings raised the question whether BRCA1 affects translation of all cytoplasmic cellular mRNAs or whether it specifically targets a subset of mRNAs. In the present study, we investigated which mRNAs are regulated by BRCA1 using a microarray analysis of polysome-associated RNAs from BRCA1-depleted MCF7 cells, a human breast cancer cell line. We isolated mRNAs from the high-molecular-weight polysomes (fractions 12 to 18) and total cellular cytoplasmic mRNAs from the cytoplasmic fraction of MCF7 cells transiently expressing either siRNA directed against BRCA1 or control siRNA. Since we were interested in identifying the mRNAs that were translationally regulated by BRCA1, we determined the relative translatability of each mRNA. The relative translatability of an mRNA was determined by normalizing the change in abundance in polysomal mRNA to the change in abundance in total cytoplasmic mRNA for each mRNA.

ORGANISM(S): Homo sapiens

SUBMITTER: Estelle DACHEUX

PROVIDER: E-GEOD-40730 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In eukaryotes, regulation of mRNA translation enables a fast, localized and finely tuned expression of gene products. Within the translation process, the first stage of translation initiation is most rigorously modulated by the actions of eukaryotic initiation factors (eIFs) and their associated proteins. These 11 eIFs catalyze the joining of the tRNA, mRNA and rRNA into a functional translation complex. Their activity is influenced by a wide variety of extra- and intracellular signals, ranging from global, such as hormone signaling and unfolded proteins, to specific, such as single amino acid imbalance and iron deficiency. Their action is correspondingly comprehensive, in increasing or decreasing recruitment and translation of most cellular mRNAs, and specialized, in targeting translation of mRNAs with regulatory features such as a 5’ terminal oligopyrimidine tract (TOP), upstream open reading frames (uORFs), or an internal ribosomal entry site (IRES). In mammals, two major pathways are linked to targeted mRNA translation. The target of rapamycin (TOR) kinase induces translation of TOP and perhaps other subsets of mRNAs, whereas a family of eIF2 kinases does so with mRNAs containing uORFs or an IRES. TOR targets translation of mRNAs that code for proteins involved in translation, an action compatible with its widely accepted role in regulating cellular growth. The four members of the eIF2 kinase family increase translation of mRNAs coding for stress response proteins such as transcription factors and chaperones. Though all four kinases act on one main substrate, eIF2, published literature demonstrates both common and unique effects by each kinase in response to its specific activating stress. This suggests that the activated eIF2 kinases regulate the translation of both a global and a specific set of mRNAs. Up to now, few studies have attempted to test such a hypothesis; none has been done in mammals. We use array analysis to determine the global mRNA shift into polysomes following a stress response, and to compare the translational response following activation of GCN2 versus PERK, two of the four eIF2alpha kinases. This SuperSeries is composed of the following subset Series:; GSE11496: Expression data from Gcn2 wild-type and knockout mouse liver perfused with or without methionine; GSE11684: Expression data from Perk wild-type and knockout mouse liver perfused without or with 2,5-di-tert-butylhydroquinone Experiment Overall Design: Refer to individual Series

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Genome-wide analysis of RNAs translationally regulated upon BRCA1 depletion in human mammary epithelial cells

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