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Role of MAPK and NF-κB signalling pathways in the regulation of the human GM-CSF gene in normal and leukaemic blood cells

Canestraro, Martina (2015)
Ph.D. thesis, University of Birmingham.

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Abstract

GM-CSF is an important haematopoietic growth factor and immune modulator. Studies on T cells revealed that efficient activation of the human GM-CSF gene is dependent upon the activation of an enhancer located 3 kb upstream of the promoter, inducible by phorbol myristate acetate and calcium ionophore (PMNI) via kinase-and Ca\(^2\)\(^+\) -dependent signalling pathways, respectively. This enhancer is often aberrantly remodelled as a constitutive DNase hypersensitive site (DHS) in acute myeloid leukaemia (AML). To investigate the role of MAPKs in enhancer activity and chromatin remodelling, I used activated T blasts and human leukaemic cell lines as inducible model systems. The combination of MEK and p38 MAPK inhibitors reduced PMNI-induced GM-CSF gene expression and the DHS at the enhancer. This was associated with a reduction in DNA-binding activity for the MAPK-inducible AP-1 and in the phosphorylation of MSK1, which in turn stimulates NF-κB transcriptional activity by phosphorylating p65 at Ser276. The combination of MEK and p38 inhibitors also reduced the PMNI-mediated recruitment of AP-1, MSK1 and NF-κB at the enhancer.

These data demonstrate a cross-talk between the MAPK and NF-κB signalling pathways in regulating GM-CSF gene transcription and therefore represent potential targets for the treatment of AML cases where aberrant chromatin remodelling occurs.

Type of Work:Ph.D. thesis.
Supervisor(s):Cockerill, Peter and Bonifer, Constanze
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Subjects:QR Microbiology
R Medicine (General)
Institution:University of Birmingham
ID Code:5720
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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