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First published online 13 May 2003
doi: 10.1242/jcs.00471

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

¹ Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA
² Department of Oncology, Catholic University of Rome, School of Medicine, Rome 00168, Italy
³ Department of Geriatric Medicine, University of Florence, School of Medicine, Florence 50139, Italy

^* Author for correspondence (e-mail: maciat{at}mmc.org)

Accepted 11 March 2003

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 represses the stress-induced export of FGF1 from NIH 3T3 cells. We report here that IL-1 is a Cu²⁺-binding protein and human U937 cells, like NIH 3T3 cells, release IL-1 in response to temperature stress in a Cu²⁺-dependent manner. We also report that the stress-induced export of IL-1 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 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 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.

Key words: Copper, Fibroblast growth factor, Interleukin 1, S100A13, Tetrathiomolybdate

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