The Met protooncogene is a transcriptional target of NFkappaB: Implications for cell survival

NFkappaB transcription factor regulates gene expression in response to extracellular stimuli such as TNF alpha. The genes regulated by NFkappaB encode for proteins which control cell growth and survival. Met is the tyrosine kinase receptor for hepatocyte growth factor, and it too promotes cell mitogenesis and survival. Previously, we showed that Met gene expression is regulated by TNF alpha. In this report, we identify and characterize a TNF alpha response element in the Met promoter. This element contains tandem C/EBP sites adjacent to an NFkappaB site. Binding of the NFkappaB p65 subunit and C/EBP beta to this element is induced by TNF alpha. To examine the interplay of NFkappaB and Met in vivo, we determined that Met mRNA and protein levels are reduced in the livers of p65-/- mice as compared to controls. In p65-/- mouse embryonic fibroblasts (MEFs), Met induction by TNF alpha is abrogated while Met's basal gene expression is reduced by half as compared to controls. When overexpressed in p65-/- MEFs, Met confers resistance to TNF-alpha-mediated cell death. Conversely, expression of dominant negative Met in wild-type MEFs renders them sensitive to cell death induced by TNF alpha. A similar response following TNF alpha challenge was observed in hepatocytic cells treated with siRNA to knockdown endogenous Met. Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival. J. Cell. Biochem. 107: 1222-1236, 2009. (C) 2009 Wiley-Liss, Inc.