Transcriptional regulation of human 26S proteasome genes

【摘要】：正The 26S proteasome,composed of the core 20S and the 19S regulatory complex,plays a central role in degradation of regulatory and abnormal proteins.Aberrant proteasome activity is directly associated with pathogenesis of certain human diseases.Recent studies have shown that Nrf1,Nrf2,heat shock factor 1 and 2 regulate the 26S proteasome gene expression in murine cells.In this study,we first demonstrated that the human proteasome genes,bearing the CCAAT box in their promoters,were regulated by the transcription factor NF-YA.NF-YA altered the basal level expression of the proteasome genes.We further found that Nrfl and Nrf2 mediated the induction of proteasome gene expression in response to proteasome inhibitor or oxidative stress.Finally,we reported that the expression of proteasome genes and proteasome activity correlates with the cell density in non-tumorigenic epithelial MCF10A cells.In particular,MCF10A cells showed spontaneous epithelial-mesenchymal transition(EMT)-like phenotypic changes depending on the condition of cell confluence.Interestingly,the change of proteasome activity is critical to the cell density-dependent EMT process.These results reveal a plasticity of proteasome gene regulation,which is important for the maintenance of proteasome homeostasis.