Professor Liu's laboratory is interested in
cancer biology and cancer pharmacology. Currently, three areas of
research are being actively pursued:
Topoisomerase I as a new molecular target for anticancer
drugs-Our studies have established that topoisomerase I is the
molecular target for camptothecin, a plant alkaloid, known to
exhibit antitumor activity against many solid tumors. We have
shown that camptothecin inhibits TOP1 by stabilizing a covalent
reaction intermediate termed the cleavable complex which
ultimately causes tumor cell death. Currently, we are
investigating the molecular basis for hTOP1 inhibition by
camptothecin and the molecular mechanism of tumor cell death.
Repair of topoisomerase I-mediated DNA damage-Topoisomerase-mediated DNA damage, which represents a
unique form of DNA damage, is important in cancer treatment and carcinogenesis. Recent studies have suggested that a
ubiquitin/proteasome pathway is involved in the repair of
topoisomerase I-mediated DNA damage. Activation of this pathway
by topoisomerase I-mediated DNA damage results in down-regulation
of topoisomerase I and hence tolerance to camptothecin. Many
solid tumor cells are defective in topoisomerase I
down-regulation, possibly due to a defect in this ubiquitin/proteasome pathway. Defect in this pathway has also
been correlated with hypersensitivity to camptothecin. Currently,
topoisomerase I-mediated DNA damage has been modeled in a yeast
system and components of this ubiqutin/proteasome pathway are
being defined genetically and biochemically. In addition to the ubiquitin/proteasome pathway, we have also demonstrated that
camptothecin activates the SUMO-1/UBC9 pathway. The roles of the ubiquitin/proteasome and SUMO-1/UBC9 pathways in the repair of
topoisomjerase-mediated DNA damage are being actively pursued in
this laboratory.
The role of topoisomerase II in tumor cell death and carcinogensis-Many of the most effective anticancer drugs in the
clinic such as etoposide and doxorubicin inhibit TOP2. The
mechanism of inhibition involves blockage of the religation
reaction of TOP2 resulting in protein-linked DNA double-strand
breaks and subsequent apoptotic cell death. We have found that
TOP2-mediated DNA damage can also be induced by physiological
stresses such as oxidative stress, thiol stress and acidic pH.
These results have suggested that TOP2-mediated DNA damage may be
an integral component of the cell death mechanism induced by
various apoptotic stimuli. The molecular mechanisms by which
these physiological stresses activate TOP2 are being
investigated.
We are also investigating the roles of topoisomerase II in carcinogenesis. The molecular mechanism of TOP2-mediated sequence
rearrangement during carcinogenesis is being investigated.
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