SYSTEMS BIOLOGY Vacillating About a Fateful Decision

Although cell signaling is often investigated as though it involved a linear response to an isolated stimulus, many receptors generate multiple––sometimes antagonistic––signals. For instance, the proapoptotic and proinflammatory cytokine tumor necrosis factor (TNF) not only activates caspases to promote cell death but also activates prosurvival mechanisms. Moreover, cells in vivo must often integrate opposing inputs from multiple stimuli. Janes et al. stimulated human colonic adenocarcinoma cells with 10 combinations of saturating or subsaturating concentrations of TNF with epidermal growth factor (EGF) or insulin to investigate crosstalk between proapoptotic and prosurvival signaling pathways. They made sequential measurements over 24 hours of 19 different intracellular signals known to be associated with TNF, EGF, or insulin signaling. Each cytokine elicited multiple classes of signals––for instance, high concentrations of TNF elicited signals associated with both TNF and EGF signaling. Surprisingly, TNF rapidly activated the EGF receptor and its downstream targets MEK and ERK about as well as did EGF. Analysis of conditioned medium and experiments with an antibody to the EGF receptor indicated that TNF rapidly stimulated the release of TGF-α (transforming growth factor-α, a prosurvival factor). Further analysis revealed the existence of an autocrine cascade: The combined effects of TNF and TGF-α led to release of the proapoptotic interleukin 1α (IL-1α, starting about 4 hours after TNF addition), which stimulated a late phase of IKK and nuclear factor B (NF-B) activation. Eight to 12 hours after TNF addition, cells began releasing the IL-1 receptor antagonist IL-1ra. Similar autocrine cascades were seen in two other epithelial cell lines. Thus, the eventual response to TNF appears to involve not only intracellular crosstalk between proapoptotic and prosurvival signaling pathways but also an autocrine cascade of pro- and antiapoptotic signals. Loewer and Lahav provide thoughtful commentary in a Preview.

K. A. Janes, S. Gaudet, J. A. Albeck, U. B. Nielsen, D. A. Lauffenburger, P. K. Sorger, The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell 124, 1225-1239 (2006). [PubMed]

A. Loewer, G. Lahav, Cellular conference call: External feedback affects cell-fate decisions. Cell 124, 1128-1130 (2006). [PubMed]

The editors suggest the following Related Resources on Science sites:

In Science Signaling

EDITORS' CHOICE
SYSTEM BIOLOGY
Predicting Responses on the Death Pathway

(13 December 2005)
Sci. STKE 2005 (314), tw448. [DOI: 10.1126/stke.3142005tw448]
 |  Abstract »

DATABASE OF CELL SIGNALING
Tumor Necrosis Factor Pathway

Guoqing Chen and David V. Goeddel
Sci. Signal. (Connections Map Pathway), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_7107
 |  Canonical Pathway »  |  Schematic »