The Met protooncogene is a transcriptional target of NF kappaB: implications for cell survival.
NF kappaB transcription factor regulates gene expression in response to extracellular stimuli such as TNF alpha. The genes regulated by NF kappaB 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 NF kappaB site. Binding of the NF kappaB p65 subunit and C/EBP beta to this element is induced by TNF alpha. To examine the interplay of NF kappaB 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 NF kappaB and that Met participates in NF kappaB-mediated cell survival.
Dai
James Y
JY
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
DeFrances
Marie C
MC
Zou
Chunbin
C
Johnson
Carla J
CJ
Zarnegar
Reza
R
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D034741:RNA, Small Interfering / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017978:Receptors, Growth Factor; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met