Regulation of the platelet-derived growth factor β-receptor
Sammanfattning: Growth factors are important signalling molecules, regulating cell growth, as well as cell movement, differentiation and apoptosis. They bind to specific receptors on the cell surface causing activation of the receptors. Activated receptors then attract adaptor molecules that brings the signal further into the cell. Aberrant regulation of growth factors and their receptors has been shown to be involved in many different diseases such as cancer, cardiovascular diseases, chronic inflammatory diseases and developmental defects. Thus, knowledge about how these growth factors and their receptor are regulated is important in understanding mechanisms for development and diseases and can be applied for development of new therapies. The Platelet-Derived Growth Factor (PDGF) is a well known mitogen in cells of mesenchymal origin as well as endothelial cells and neurons. PDGF is most important during embryonal development. There are four different isoforms of PDGF binding two homologous receptors, the a- and the b-receptor, with different affinity. This thesis describes how the PDGF b-receptor can be regulated by alteration of its kinase activity, and by transcriptional mechanisms. It also describes an aberrant activity of PDGF in tumour cell lines of medulloblastomas. PDGF is a potent inflammatory cytokine and in order to estimate its regulation during inflammation the cross talk between PDGF b-receptor and another pro-inflammatory molecule, TNF-a was examined It was found that TNF-a suppresses the PDGF b-receptor kinase without altering its expression. Overexpression of PDGF in tumours is often reported. Characterisation of the function is, however, much less described. These findings indicate that the expression of PDGF and PDGF receptors in medulloblastoma cells reflects the early neuronal differentiation stage of these cells. They also suggest the presence of an autocrine PDGF stimulatory loop affecting PDGF a-receptor in medulloblastoma cells.The PDGF b-receptor promoter is tightly controlled by NF-Y that binds to a CCAAT box located upstream of the initiation site. Myc plays a key role in the cell-cycle dependent expression of PDGF b-receptor mRNA. In this thesis it is shown that c-Myc binds NF-Y subunits, YB and YC. The HAP domains of NF-YB and NF-YC, and that the Myc homology boxes are indispensable for the interaction and also for the repression of PDGF b-receptor transcription. Furthermore, the activity of NF-Y becomes suppressed by this interaction. Furthermore, this thesis shows that Sp1 enhances PDGF b-receptor promoter activity. Deletion of the GC-rich region resulted in a 50% decrease of the transcriptional activity, and a complete loss of its responsiveness to Sp1. When the Sp1 binding sites were deleted from the promoter transfection of NF-Y failed to enhance the promoter activity, suggesting an important role for Sp1 in this NF-Y controlled transcription.
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