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

[摘要] 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.

[发布机构] University:University of Birmingham;Department:School of Immunity and Infection

[关键词] Q Science;QR Microbiology