期刊
JOURNAL OF CELL SCIENCE
卷 116, 期 13, 页码 2687-2696出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.00471
关键词
copper; fibroblast growth factor; interleukin 1; S100A13; tetrathiomolybdate
类别
资金
- NCRR NIH HHS [RR 15555] Funding Source: Medline
- NHLBI NIH HHS [HL 32348, HL 35627] Funding Source: Medline
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-1alpha represses the stress-induced export of FGF1 from NIH 3T3 cells. We report here that IL-1alpha is a Cu2+-binding protein and human U937 cells, like NIH 3T3 cells, release IL-1alpha in response to temperature stress in a Cu2+- dependent manner. We also report that the stress-induced export of IL-1alpha 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-1alpha release, whereas the expression of wildtype S100A13 functions to eliminate the requirement for stress-induced transcription. Lastly, we present biophysical evidence that IL-1alpha 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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