Novel apoptosis mediated by inflammation‐associated fibronectin fragments is effected by proteasomal degradation of p53 in an mdm2‐dependent manner

Abstract

The extracellular matrix (ECM) plays an important role in cellular processes including growth, differentiation and survival. Degradation of ECM components as occurs in inflammatory diseases, such as periodontal disease, can trigger apoptosis in the adjacent cells and the induction of alternate signaling pathways. In periodontal disease, bacterial proteases degrade the ECM, thus releasing matrix fragments into the diseased environment. Previously, we showed that fibronectin fragments induce a novel pathway of apoptosis that involves increased phosphorylation of c-Jun N-terminal kinase and down regulation of p53 in periodontal ligament (PDL) cells. This decrease in p53 levels was in part due to transcriptional downregulation. Here, we report that an additional decrease in p53 levels is mediated by proteasomal degradation. PDL cells showed a dose-dependent decrease in p53 levels in the presence of an altered fibronectin matrix, and when pretreated with MG-132, a proteasome inhibitor, the degradation of p53 was arrested. Moreover, the degradation of p53 in this pathway is an mdm-2 regulated process, since overexpressing an mdm-2 mutant lacking the p53 binding site, limits the decrease in p53 levels. This data indicate that stressful conditions, such as the perpetuation of degraded matrices as occur during inflammation, trigger apoptosis of cells by decreasing the levels of p53, both transcriptionally and by proteasomal degradation that is mdm2-dependent. This research was funded by NIH Grant R01 DE13725 to YLK.