CREB-dependent gene regulation by prion protein: Impact on MMP-9 and β-dystroglycan

Corruption of the normal function of the cellular prion protein (PrPC) by the scrapie isoform (PrPSc) emerges as a critical causal event in Transmissible Spongiform Encaphalopathies (TSE) pathogenesis. However, PrPC physiological role remains unclear. By exploiting the properties of the 1C11 neuroectodermal cell line, able to convert into 1C11(5-HT) serotonergic or 1C11(NE) noradrenergic neuronal cells, we assigned a signaling function to PrPC. Here, we establish that antibody-mediated PrPC ligation promotes the recruitment of the cAMP responsive element binding protein (CREB) transcription factor downstream from the MAPK ERK1/2, in 1C11 precursor cells and their 1C11(5-HT) and 1C11(NE) neuronal progenies. Whatever the differentiation state of 1C11 cells, the PrPC-dependent CREB activation triggers Egr-1 and c-fos transcription, two immediate early genes that relay CREB's role in cell survival and proliferation as well as in neuronal plasticity. Furthermore, in 1C11 derived neuronal cells, we draw a link between the PrPC-CREB coupling and a transcriptional regulation of the metalloproteinase MMP-9 and its inhibitor-TIMP-1, which play pivotal roles in neuronal pathophysiology. Finally, the PrPC-dependent control on MMP-9 impacts on the processing of the transmembrane protein, beta-dystroglycan. Taken together, our data define Molecular mechanisms that likely mirror PrPC ubiquitous contribution to cytoprotection and its involvement in neuronal plasticity. (c) 2008 Elsevier Inc. All rights reserved.