TY - JOUR
T1 - Atypical multidrug resistance may be associated with catalytically active mutants of human DNA topoisomerase II α
AU - Okada, Yoshito
AU - Tosaka, Aki
AU - Nimura, Yuji
AU - Kikuchi, Akihiko
AU - Yoshida, Shonen
AU - Suzuki, Motoshi
N1 - Funding Information:
We are grateful to the people in Laboratory of Cancer Cell Biology for helpful discussion. This study was supported by Grants-in Aid from the Ministry of Education, Science, Sports and Culture of Japan to AK, SY and YN, and by Yokoyama and Aichi Cancer Research Foundations to MS.
PY - 2001/7/11
Y1 - 2001/7/11
N2 - In human cells, atypical drug resistance was previously identified with reduced catalytic activity or nuclear localization efficiency of DNA topoisomerase IIα (TOP2α). We have shown two etoposide resistant hTOP2α mutants, K798L and K798P confer resistance to etoposide. In this work, we showed these mutants are also resistant against doxorubicin and mAMSA in vivo in the yeast strain ISE2, rad52, top2-4 at the non-permissive temperature. We purified these mutants to characterize the drug resistant mechanism. Purified recombinant proteins were 8- to 12-fold more resistant to etoposide and doxorubicin than wild type TOP2α, and 2-fold more resistant to amsacrine, as measured by accumulation of cleavable DNA. These data show that K798L and K798P may be intrinsically resistant against these drugs in vitro and that this character may confer atypical multidrug resistant phenotype in vivo in yeast.
AB - In human cells, atypical drug resistance was previously identified with reduced catalytic activity or nuclear localization efficiency of DNA topoisomerase IIα (TOP2α). We have shown two etoposide resistant hTOP2α mutants, K798L and K798P confer resistance to etoposide. In this work, we showed these mutants are also resistant against doxorubicin and mAMSA in vivo in the yeast strain ISE2, rad52, top2-4 at the non-permissive temperature. We purified these mutants to characterize the drug resistant mechanism. Purified recombinant proteins were 8- to 12-fold more resistant to etoposide and doxorubicin than wild type TOP2α, and 2-fold more resistant to amsacrine, as measured by accumulation of cleavable DNA. These data show that K798L and K798P may be intrinsically resistant against these drugs in vitro and that this character may confer atypical multidrug resistant phenotype in vivo in yeast.
UR - https://www.scopus.com/pages/publications/0035845016
UR - https://www.scopus.com/pages/publications/0035845016#tab=citedBy
U2 - 10.1016/S0378-1119(01)00554-6
DO - 10.1016/S0378-1119(01)00554-6
M3 - Article
C2 - 11470519
AN - SCOPUS:0035845016
SN - 0378-1119
VL - 272
SP - 141
EP - 148
JO - Gene
JF - Gene
IS - 1-2
ER -