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AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2.

ABSTRACT: AU-rich elements (AREs), present in mRNA 3'-UTRs, are potent posttranscriptional regulatory signals that can rapidly effect changes in mRNA stability and translation, thereby dramatically altering gene expression with clinical and developmental consequences. In human cell lines, the TNFalpha ARE enhances translation relative to mRNA levels upon serum starvation, which induces cell-cycle arrest. An in vivo crosslinking-coupled affinity purification method was developed to isolate ARE-associated complexes from activated versus basal translation conditions. We surprisingly found two microRNP-related proteins, fragile-X-mental-retardation-related protein 1 (FXR1) and Argonaute 2 (AGO2), that associate with the ARE exclusively during translation activation. Through tethering and shRNA-knockdown experiments, we provide direct evidence for the translation activation function of both FXR1 and AGO2 and demonstrate their interdependence for upregulation. This novel cell-growth-dependent translation activation role for FXR1 and AGO2 allows new insights into ARE-mediated signaling and connects two important posttranscriptional regulatory systems in an unexpected way.

SUBMITTER: Vasudevan S

PROVIDER: S-EPMC3430382 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2.

Vasudevan Shobha S Steitz Joan A JA

Cell 20070301 6

AU-rich elements (AREs), present in mRNA 3'-UTRs, are potent posttranscriptional regulatory signals that can rapidly effect changes in mRNA stability and translation, thereby dramatically altering gene expression with clinical and developmental consequences. In human cell lines, the TNFalpha ARE enhances translation relative to mRNA levels upon serum starvation, which induces cell-cycle arrest. An in vivo crosslinking-coupled affinity purification method was developed to isolate ARE-associated c ...[more]

PMID: 17382880

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Project description:The yeast M-NM-6-crystallin Zta1p interacts specifically with RNA sequences rich in adenine and uracil (AU-rich element). We have looked for possible targets of Zta1p through a comparative transcriptional analysis of the yeast defective in ZTA1 (M-NM-^Tzta1) versus the wild-type by microarray. This revealed that a group of genes implicated on amino acid biosynthesis are affected by the lack of ZTA1. The effect on one of the targets ARG4 was studied in more detail, revealing a clear positive correlation between ZTA1 and ARG4 expression at the mRNA level. We demonstrate that Zta1p is able to bind specifically to the 3M-bM-^@M-^YUTR AU-rich elements of ARG4 mRNA in vitro, suggesting that the mechanism by which ZTA1 modulates the expression of ARG4 is probably mediated by this mRNA binding ability. Moreover, the expression of ZTA1 is also under the control of the TOR pathway, and under Gcn4p, which regulates genes implicated in the response to nutrient availability and the general amino acid control (GAAC). In summary, our results shed light on the functional role of the M-NM-6-crystallin family as stress response proteins, with a conserved functional role, from yeast to humans, in the post-transcriptional regulation of genes that need to be rapidly activated for cell defense. Triplicate biological replicate experiments were performed, where the two strains, M-bM-^HM-^Fzta1 and wild-type, were grown in the presence or absence of hydrogen peroxide. The experimental design was defined to directly compare the M-bM-^HM-^Fzta1 versus the wild-type strain in either of the two hydrogen peroxide treatment conditions (i.e. treated M-bM-^HM-^Fzta1 versus treated wt, or untreated M-bM-^HM-^Fzta1 versus untreated wt). A duplicate hybridization on a separate array with dye swapping was performed in each case to correct for dye bias effects. Thus, a total of 12 array data sets were produced as a result of processing three experimental pairs of samples, for each of two treatment conditions, with dye swap duplicates.

Dataset Information

AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2.

Publications

AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2.

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