Role of Drug-Induced Fas Ligand Expression in Breast Tumor Progression
Abstract
Fas/FasL is a key regulator of apoptosis. In the past year, we have been trying to determine whether FasL is induced in vivo by anticancer agents. Although we did not detect any significant induction of FasL by VP-16 or doxorubicin, we found that Daxx, a Fas-associated protein, interacts with UBC9 that is implicated in regulating the subcellular localization of targeted proteins. Since only the cytosolic Daxx, not nuclear Daxx, is involved in enhancing Fas-mediated apoptosis, the regulation of the subcellular localization of Daxx is a key for its action. We found that while topoisomerase (topo) II inhibitors up-regulate Daxx, the same drugs reduce the binding ability of Daxx to UBC9, suggesting that the drugs may exert their impact on the subcellular localization of Daxx through UBC9. Furthermore, we showed that overexpression of a dominant negative UBC9 sensitizes cells to topo inhibitors, whereas resistance of tumor cells to cis-platin is associated with up-regulation of UBC9, suggesting a possible role of UBC9 in drug responsiveness. Consequently, further investigation on the interaction of Daxx and UBC9 in the context of the subcellular localization of Daxx and drug responsiveness may provide insight into the molecular mechanism by which Daxx enhances Fas-mediated apoptosis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2001
- Accession Number
- ADA403606
Entities
People
- William T. Beck
Organizations
- University of Illinois at Chicago