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JCS ePress online publication date 13 May 2003
doi: 10.1242/jcs.00471

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Research Article

S100A13 mediates the copper-dependent stress-induced release of IL-1{alpha} from both human U937 and murine NIH 3T3 cells


Anna Mandinova, Raffaella Soldi, Irene Graziani, Cinzia Bagalá, Stephen Bellum, Matteo Landriscina, Francesca Tarantini, Igor Prudovsky, and Thomas Maciag*
* Author for correspondence (e-mail: maciat{at}mmc.org)

Copper is involved in the promotion of angiogenic and inflammatory events in vivo and, although recent clinical data has demonstrated the potential of Cu2+ chelators for the treatment of cancer in man, the mechanism for this activity remains unknown. We have previously demonstrated that the signal peptide-less angiogenic polypeptide, FGF1, uses intracellular Cu2+ to facilitate the formation of a multiprotein aggregate that enables the release of FGF1 in response to stress and that the expression of the precursor form but not the mature form of IL-1{alpha} represses the stress-induced export of FGF1 from NIH 3T3 cells. We report here that IL-1{alpha} is a Cu2+-binding protein and human U937 cells, like NIH 3T3 cells, release IL-1{alpha} in response to temperature stress in a Cu2+-dependent manner. We also report that the stress-induced export of IL-1{alpha} involves the intracellular association with the Cu2+-binding protein, S100A13. In addition, the expression of a S100A13 mutant lacking a sequence novel to this gene product functions as a dominant-negative repressor of IL-1{alpha} release, whereas the expression of wild-type S100A13 functions to eliminate the requirement for stress-induced transcription. Lastly, we present biophysical evidence that IL-1{alpha} may be endowed with molten globule character, which may facilitate its release through the plasma membrane. Because Cu2+ chelation also represses the release of FGF1, the ability of Cu2+ chelators to potentially serve as effective clinical anti-cancer agents may be related to their ability to limit the export of these proinflammatory and angiogenic signal peptide-less polypeptides into the extracellular compartment.


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