Signaling pathways mediated by tumor necrosis factor a

K.G. Leong1 and A. Karsan1,2

Departments of 1Experimental Medicine and 2Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Offprint requests to: Aly Karsan, Department of Pathology and Laboratory Medicine, UBC McDonald Research Laboratories, St. Paul's Hospital, Room B292, 1081 Burrard St., Vancouver, BC. Canada V6Z 1Y6. e-mail: akarsan@mrl.ubc.ca

 

Summary. Tumor necrosis factor a (TNFa) has been shown to trigger many signaling pathways. Following oligomerization by TNFa, the receptors TNF-RI and TNF-RII 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. Two 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. Histol. Histopathol. 15, 1303-1325 (2000)

Key words: Tumor necrosis factor, Signal transduction, Apoptosis, NFkB, AP-1


DOI: 10.14670/HH-15.1303