Signaling pathways mediated by tumor necrosis factor a

Abstract

Tumor necrosis factor a (TNFa) has been shown to trigger many signaling pathways. Following oligomerization by TNFa, the receptors TNF-RI and TNF-RI1 associate with adapter molecules via specific protein-protein interactions. The subsequent recruitment of downstream molecules to the receptor complex enables propagation of the TNFa signal. l k o cellular responses to TNFa have been well documented, the induction of cell death and the activation of gene transcription for cell survival. TNFa-induced apoptosis involves the activation of caspase cascades, which culminate in the cleavage of specific cellular substrates to effect cell death. TNFa has also been implicated in various caspase-independent cell death processes. Two transcription factors activated by TNFa are nuclear factor KB (NFKB) and activating protein 1 (AP-1). Pathways that promote the activation of these transcription factors involve signaling molecules such as kinases, phospholipases, and sphingomyelinases. In addition to increased survival (anti-apoptotic) gene expression, NFKB and AP-1 also induce the expression of genes involved in inflammation, cell growth, and signal regulation. The past decade has witnessed the identification of numerous signaling intermediates implicated in TNFa cellular responses. This article reviews the molecular mechanisms of TNFa signal transduction. In particular, pathways involved in cell death and transcription factor activation are discussed.