Angiogenesis is a prerequisite for solid tumor growth and metastasis. 
Elucidation of the signaling pathways that control tumor angiogenesis 
constitutes the basis for a rational antiangiogenic tumor therapy. Here we show 
that the production of vascular endothelial growth factor (VEGF) in HeLa and 
HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome 
(CSN). The CSN is a kinase complex that cooperates with the ubiquitin/26S 
proteasome system in regulating the stability of proteins involved in signal 
transduction. VEGF expression is controlled by the transcription factors 
activator protein (AP)-1, AP-2, SP-1, and hypoxia-inducible factor 1. Inhibition 
of CSN kinase activity by 50 microM curcumin for 2 h decreases the cellular 
c-Jun concentration, resulting in a reduction of the VEGF production by 
approximately 75%. The removal of the inhibitor from the cells led to a 
time-dependent recovery of endogenous c-Jun that is paralleled by increasing 
VEGF production. Elevated cellular CSN activity induced by CSN subunit 2 
overexpression causes increased VEGF production in HeLa cells. A competitor of 
CSN-dependent c-Jun phosphorylation, the NH(2)-terminal c-Jun fragment 
Deltac-Jun(1-226), inhibits VEGF production in HeLa cells. The transcription 
factors AP-2 and SP-1 act independently of the CSN. They contribute less than a 
quarter to basal VEGF production. Under our experimental conditions, 
hypoxia-inducible factor 1alpha protein was not detected. Overexpression of the 
tumor suppressor p53 reduces VEGF production in HeLa cells. p53 competes with 
c-Jun for CSN-specific phosphorylation with the consequence of c-Jun 
destabilization. We conclude that CSN-directed c-Jun signaling mediates high 
VEGF production in HeLa and HL-60 cells. The data provide an explanation for the 
known antiangiogenic and antitumorigenic activities of curcumin. Because the CSN 
regulates the major part of VEGF production in the tested tumor cells, it 
constitutes a potentially important target for tumor therapy.