Untranslated Region

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Jack T. Rogers - One of the best experts on this subject based on the ideXlab platform.

Joanna Floros - One of the best experts on this subject based on the ideXlab platform.

John E. Hesketh - One of the best experts on this subject based on the ideXlab platform.

  • mRNA localization by a 145-nucleotide Region of the c-fos 3'--Untranslated Region. Links to translation but not stability.
    Journal of Biological Chemistry, 2001
    Co-Authors: Gillian Dalgleish, Jean-marie Blanchard, Jean-luc Veyrune, John E. Hesketh
    Abstract:

    Abstract The presence of a localization signal in the 3′-Untranslated Region of c-fos mRNA was investigated by in situ hybridization and cell fractionation techniques. Cells were transfected with chimeric gene constructs in which the β-globin coding Region was used as a reporter and linked to either its own 3′-Untranslated Region, the c-fos 3′-Untranslated Region, or the c-fos 3′-Untranslated Region containing different deletions. Replacement of the endogenous β-globin 3′-Untranslated Region by that from c-fos caused a redistribution of the transcripts so that they were recovered in cytoskeletal-bound polysomes and seen localized in the perinuclear cytoplasm. Deletion of the AU-rich instability Region did not affect transcript localization, but removal of a distinct 145-nucleotide Region of the 3′-Untranslated Region abolished it. The prevention of transcript translation by desferrioxamine led to a marked loss of transcript localization, independent of mRNA instability. The data show that the 3′-Untranslated Region of c-fos mRNA, as c-myc, contains a localization signal, which targets the mRNA to the perinuclear cytoskeleton. We propose that this is important to ensure efficient nuclear import of these key regulatory proteins. mRNA localization by the fos3′-Untranslated Region is independent of mRNA instability, and the two are determined by different regulatory elements.

  • The 3′ Untranslated Region plays a role in the targeting of metallothionein-I mRNA to the perinuclear cytoplasm and cytoskeletal-bound polysomes
    Biochimica et biophysica acta, 1997
    Co-Authors: Patrick Mahon, L. Anne Glover, Kris Partridge, John H. Beattie, John E. Hesketh
    Abstract:

    Abstract The mechanism of localisation of metallothionein-I (MT-I) mRNA was studied in transfected cells by in situ hybridisation and cell fractionation. Hepatoma cells were transfected with the 5′-Untranslated Region and coding Region of the β-globin gene alone or linked to either the β-globin 3′-Untranslated Region (3′-UTR) or the MT-I 3′-UTR. The wild-type β-globin mRNA and the β-globin mRNA lacking its native 3′-UTR were present in free and cytoskeletal-bound polysomes to a similar extent and showed no localisation. Chimaeric globin-metallothionein transcripts were significantly enriched in cytoskeletal-bound polysomes and were localised in the perinuclear cytoplasm. Chimaeric globin-metallothionein and wild-type globin transcripts were of similar stability. Chinese Hamster Ovary cells were transfected with constructs in which the MT-I 5′-Untranslated Region and coding sequences were linked to either the endogenous 3′-UTR or the glutathione peroxidase 3′-UTR. Wild-type MT-I transcripts were localised in the perinuclear cytoplasm but the chimaeric MT-I-glutathione peroxidase transcripts showed no distinct localisation. The results indicate that the 3′-UTR of MT-I mRNA contains a localisation signal which promotes both the association of the mRNA with the cytoskeleton and its perinuclear localisation.

  • Evidence for a localisation signal in the 3'-Untranslated Region from vimentin messenger RNA.
    The International Journal of Biochemistry & Cell Biology, 1997
    Co-Authors: John W. Wiseman, L. Anne Glover, John E. Hesketh
    Abstract:

    Abstract There is increasing evidence that some mRNAs are localised in eukaryotic somatic cells, but it is unclear what proportion of mRNAs are localised and whether this sorting involves 3′-Untranslated sequences. The presence of a localisation signal within the 3′-Untranslated Region of vimentin mRNA was investigated by studying mRNA distribution in fibroblasts transfected with β-globin and hybrid globin-vimentin gene constructs. In cells transfected with constructs containing either a fragment of the rabbit β-globin gene containing both coding sequences and 3′-Untranslated Region or the β-globin coding sequences alone in situ hybridisation showed that β-globin mRNA was distributed throughout the cytoplasm without any evident localisation. In contrast, in cells transfected with globin coding sequences linked to the vimentin 3′-Untranslated Region there was a strong perinuclear localisation of the hybrid mRNA. The results show that loss of its endogenous 3′-Untranslated Region does not affect distribution of β-globin mRNA whereas the vimentin 3′-Untranslated Region causes an altered localisation of β-globin mRNA. We conclude that the vimentin 3′-Untranslated Region contains a localisation signal which can direct reporter sequences to the perinuclear cytoplasm.

  • A localisation signal in the 3' Untranslated Region of c-myc mRNA targets c-myc mRNA and beta-globin reporter sequences to the perinuclear cytoplasm and cytoskeletal-bound polysomes.
    Journal of cell science, 1996
    Co-Authors: Jean-luc Veyrune, J. M. Blanchard, G P Campbell, J. Wiseman, John E. Hesketh
    Abstract:

    There is increasing evidence that in mammalian cells some mRNAs are localised to specific parts of the cytoplasm and a proportion of mRNAs and polyribosomes are associated with the cytoskeleton. It has been shown previously that c-myc mRNA is present in the perinuclear cytoplasm and associated with the cytoskeleton, and that this localisation is dependent upon the 3' Untranslated Region of the mRNA. The present studies show that in transfected fibroblasts the c-myc 3' Untranslated Region is able to localise beta-globin reporter sequences to the perinuclear cytoplasm. Studies with constructs containing deletions within the 3' Untranslated Region identify the Region between bases 194 and 280 as critical for localisation. Transfection of cells with constructs in which this Region is linked to beta-globin sequences showed that it was sufficient to localise the chimaeric transcripts to the perinuclear cytoplasm and to cytoskeletal-bound polyribosomes. Transfection with constructs containing a mutated AUUUA sequence within the 194-280 base Region showed that this conserved AUUUA is required for targeting of both c-myc mRNA and a chimaeric transcript of beta-globin transcripts linked to the c-myc 3' Untranslated Region. The Region between bases 194 and 280 did not induce instability of beta-globin transcripts and the AUUUA mutation had little effect upon mRNA stability. We propose that this 86 nt Region of the 3' Untranslated Region contains a localisation signal to target c-myc mRNA so that it is retained on cytoskeletal-bound polysomes in the perinuclear cytoplasm; a conserved AUUUA sequence appears to be a critical part of this signal.

  • Targeting of c-myc and β-globin coding sequences to cytoskeletal-bound polysomes by c-myc 3′ Untranslated Region
    Biochemical Journal, 1994
    Co-Authors: John E. Hesketh, Marc Piechaczyk, Gillian Patricia Campbell, J. M. Blanchard
    Abstract:

    The influence of the 3' Untranslated Region on mRNA localization was investigated by measuring the distribution of myc, beta-globin and hybrid myc-globin mRNAs between free, cytoskeletal-bound and membrane-bound polysomes in cells transfected with either control or chimeric gene constructs. c-myc sequences and beta-globin-coding sequences linked to the myc 3' Untranslated Region were present at greatest enrichment in cytoskeletal-bound polysomes. beta-Globin mRNA and myc-coding sequences linked to the beta-globin 3' Untranslated Region were recovered largely in the free polysomes. In situ hybridization confirmed that replacement of the c-myc 3' Untranslated Region by that of globin caused a relocalization of the mRNA. The results suggest that mRNA localization in differentiated eukaryotic cells depends on a mechanism that involves directional information in the 3' Untranslated Region of mRNAs.

Avi L. Friedlich - One of the best experts on this subject based on the ideXlab platform.

George C Tsokos - One of the best experts on this subject based on the ideXlab platform.

  • Polymorphisms/Mutations of TCR-ζ-Chain Promoter and 3′ Untranslated Region and Selective Expression of TCR ζ-Chain with an Alternatively Spliced 3′ Untranslated Region in Patients with Systemic Lupus Erythematosus
    Journal of Autoimmunity, 2001
    Co-Authors: Madhusoodana P. Nambiar, Vishal G. Warke, Gary M. Kammer, Sandeep Krishnan, Edith J Enyedy, Gregory J Dennis, George C Tsokos
    Abstract:

    A vast majority of systemic lupus erythematosus (SLE) patients display decreased expression of TCR zeta-chain mRNA, a critical signaling molecule implicated in the selection of the TCR repertoire and in the prevention of autoimmunity. To identify the molecular mechanisms involved in the downregulation of TCR zeta-chain transcripts in SLE T cells, we investigated the possibility of polymorphisms/mutations in the promoter and the 3' Untranslated Region. PCR, cloning and sequence analysis of the promoter Region from the genomic DNA showed significantly higher number of polymorphisms in SLE T cells compared to non-SLE control subjects (P = 0.044). Promoter sequence was also analysed from granulocytes to delineate the possibility of somatic mutations in activated SLE T cells. Promoter polymorphisms were significantly higher in granulocytes of SLE patients compared to non-SLE controls (P = 0.048), suggesting that these polymorphisms were of genomic origin. Nucleotide analysis of the promoter sequence revealed a -76T insertion compared to the published sequence, in all of the SLE samples and controls. RT-PCR analysis of the TCR zeta-chain 3' Untranslated Region showed a 344 bp product in addition to the expected 906 bp product. Cloning and sequence analysis of the 344 bp product indicated that it is an alternatively spliced form with both splicing donor and acceptor sites, resulting in deletion of nucleotides 672-1233 of TCR zeta-chain mRNA. Unlike the nomal TCR zeta-chain, the expression of TCR zeta-chain with the alternatively spliced 344 bp 3' Untranslated Region was higher in SLE T cells compared to non-SLE controls. The number of mutations/polymorphisms in the 906 bp TCR zeta-chain 3' Untranslated Region were significantly higher in SLE T cells compared to non-SLE subjects (P = 0.032). Frequent mutations/polymorphisms and aberrant splicing of the downstream 3' Untranslated Region may affect the stability and/or transport of TCR zeta-chain mRNA, leading to its downregulation in SLE T cells.

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