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Title: Structural, functional and mechanistic analysis of the Bag-1 internal ribosome entry site
Authors: Pickering, Becky M.
Award date: 2003
Presented at: University of Leicester
Abstract: Bag-1 is an anti-apoptotic protein involved in the regulation of a number of cellular processes, notably as a co-chaperone for the 70kDa heat shock proteins. At least four protein products of Bag-1 have been isolated, p50, p46, p36 and a minor isoform, p29. The 5' UTR of the p36 isoform of Bag-1 has been shown to contain an internal ribosome entry segment (IRES). The internal ribosome entry mediated mechanism of translation has been shown to maintain Bag-1 expression when cap- dependent translation is compromised during heat shock. Many IRESes require trans-acting protein factors for optimal IRES activity. Bag-1 IRES activity is cell-type specific and is inefficient in cell lines with low endogenous levels of the /r<ms-acting factors poly (rC) binding protein 1 (PCBP1) and polypyrimidine tract binding protein 1 (PTB1). Activity of the Bag-1 IRES can be stimulated in vitro and in vivo by overexpression of PTB and PCBP1. PTB and PCBP1 bind specifically to the minimal active Bag-1 IRES element. A secondary structural model of the minimal Bag-1 IRES was obtained by chemical and enzymatic probing of IRES RNA in vitro. Addition of PTB and PCBP1 modulates the secondary structure of the Bag-1 IRES in the ribosome-landing region. Overexpression of Bag-1 proteins in cells subjected to genotoxic stress has been shown to protect cells from stress-induced growth inhibition and cell death. The Bag-1 IRES is functional in heat-shocked cells and cells treated with chemotherapeutic agents and this correlates with a redistribution of PTB and PCBP1 from the nucleus of the cell to the cytoplasm. A model for the mechanism of action of the Bag-1 IRES and the influence of PTB and PCBP1 is proposed.
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, Dept. of Biochemistry
Leicester Theses

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