Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently cloned the full-length cDNA of a tumour-associated protein. The recombinant protein expressed in bacteria and referred to as angiocidin has potent antitumour activity in vivo and in vitro. Angiocidin inhibits tumour growth and angiogenesis by inducing apoptosis in endothelial cells. Based on the sequence similarity of angiocidin to S5a, one of the major polyubiquitin recognition proteins in eukaryotic cells, we postulated that the antiendothelial activity of angiocidin could be due in part to its polyubiquitin binding activity. In support of this hypothesis, we show that angiocidin binds polyubiquitin in vivo with high affinity and colocalises with ubiquitinated proteins on the surface of endothelial cells. Binding is blocked with an antiubiquitin antibody. Angiocidin treatment of endothelial cells transfected with a proteasome fluorescent reporter protein showed a dose-dependent inhibition of proteasome activity and accumulation of polyubiquitinated proteins. Full-length angiocidin bound polyubiquitin while three angiocidin recombinant proteins whose putative polyubiquitin binding sites were mutated either failed to bind polyubiquitin or had significantly diminished binding activity. The in vitro apoptotic activity of these mutants correlated with their polyubiquitin binding activity. These data strongly argue that the apoptotic activity of angiocidin is dependent on its polyubiquitin binding activity.
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PMID:Endothelial apoptotic activity of angiocidin is dependent on its polyubiquitin binding activity. 1622 12

Angiocidin, a protein over-expressed in many different solid tumors and tumor capillary endothelial cells inhibits angiogenesis and tumor growth [Zhou, J., et al., 2004. Cloning and characterization of angiocidin, a tumor cell binding protein for thrombospondin-1. J Cell Biochem. 92, 125-146]. Since several splice variants of angiocidin have distinct biochemical functions in membrane transport and protein degradation, we sought to evaluate the function of endogenously expressed angiocidin in human umbilical vein endothelial (HUVE) cells using siRNA. We observed a 90% reduction of the target mRNA levels after 24 h. Endogenous angiocidin protein expression was reduced by 80% after three days, as evaluated by Western blot analysis. We also found that anti-angiocidin siRNA down-regulated 90% of the protein expression of matrix metalloproteinase 2 (MMP-2) and 50% of its gelatinolytic activity. Reduction of endogenous angiocidin completely inhibited endothelial cord formation on Matrigel. Cells expressing low levels of angiocidin grew more slowly, were less invasive and less adhesive than control cells. Consistent with the reported function of one of the angiocidin analogues S5a, we found that the expression of polyubiquitinated proteins was higher in anti-angiocidin siRNA-treated cells as compared to normal and control siRNA-treated cells. These results suggest that endogenous angiocidin and its homologues promote endothelial cell invasion, adhesion, and angiogenesis through mechanisms involving polyubiquitin-dependent protein degradation and MMP-2 expression.
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PMID:Reduction of angiocidin expression in human umbilical vein endothelial cells via siRNA silencing inhibits angiogenesis. 1690 4