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    Tumor necrosis factor-alpha posttranscriptional gene expression regulation and messenger ribonucleic acid poly(A) tail metabolism in macrophages

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    Author
    Crawford, Eric Keith
    Advisor
    Hasday, Jeffrey D.
    Date
    1996
    Type
    dissertation
    
    Metadata
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    Abstract
    Tumor necrosis factor-alpha (TNF-alpha)is both essential for host survival and potentially fatal if inappropriately expressed. The extreme and divergent actions of TNF-alpha underscore the importance of understanding the mechanisms that regulate its expression. TNF-alpha expression in macrophages is regulated at the levels of transcript initiation and elongation, but transcriptional control appears to have a lesser role in TNF-alpha regulation than posttranscriptional processes. Despite ongoing basal TNF-alpha transcription, TNF-alpha messenger ribonucleic acid (mRNA) is not translated in resting macrophages, but following cell activation, translational efficiency increases several hundred fold. Most eukaryotic transcripts are 3' polyadenylated during intranuclear mRNA processing. The poly(A) tail generally stabilizes mRNA and enhances ribosome recruitment and translational efficiency. In oocytes and embryos, rapid cytoplasmic poly(A) tail shortening and elongation are used to orchestrate expression of some gene transcripts. In this work we show that in resting macrophages, cytoplasmic TNF-alpha mRNA has a markedly attenuated or absent poly(A) tail and is not associated with ribosomes. Following stimulation with lipopolysaccharide (LPS), fully adenylated and polysome associated TNF-alpha mRNA appears coincident with onset of TNF-alpha protein synthesis. Macrophages contains no detectable stores of TNF-alpha protein, yet in cells pretreated with actinomycin D to block new transcription, LPS induces a gradual increase in length of the cytoplasmic pool of hypoadenylated TNF-alpha mRNA as well as secretion of TNF-alpha protein. These data suggest that removal of the poly(A) tail blocks initiation of translation in unstimulated macrophages and LPS inactivates this process allowing synthesis of translatable polyadenylated TNF-alpha mRNA. We propose that the increase in size of cytoplasmic TNF-alpha mRNA and subsequent TNF-alpha protein secretion, in the presence of transcriptional inhibition, is due to cytoplasmic readenylation and translation of the readenylated transcript. Readenylation of preformed hypoadenylated TNF-alpha mRNA may provide the macrophage with an alternative pathway for producing small amounts of TNF-alpha.
    Description
    University of Maryland, Baltimore. Pathology. Ph.D. 1996
    Keyword
    Biology, Molecular
    Biology, Cell
    messenger ribonucleic acid poly(A)
    Macrophages
    Poly A--metabolism
    RNA Processing, Post-Transcriptional
    Tumor Necrosis Factor-alpha--genetics
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1447
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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