@entity19 thymoma cell lines expressing mutated forms of the @entity21651 P-glycoprotein were isolated using a novel @entity3907 -based P-glycoprotein inhibitor @entity70125 ( @entity70125 ). The selection strategy required resistance to a combination of @entity70125 and @entity3812 . Five mutations were identified ( @entity70126 , @entity70127 , @entity70128 , @entity70129 , and @entity70130 ) that reduce the capacity of @entity70125 to inhibit P-glycoprotein-dependent drug resistance. These mutations also result in a loss of @entity1311 resistance ranging from 47 to 100%. Four mutations are located in the second half of the protein, within or near the proposed transmembrane segment (TMS) 10--11 regions. The fifth mutation ( @entity70126 ) is within the first half of the protein, proximal (cytoplasmic) to TMS 6. The variant cell line expressing the @entity70129 mutation was subjected to a second round of selection involving @entity70125 and the toxic drug @entity5808 . This resulted in the isolation of a cell line expressing a P-glycoprotein with a double mutation. The additional mutation ( @entity70131 ) is located within TMS 12 and conveys further decreases in resistance to @entity1311 and the capacity of @entity70125 to inhibit drug resistance. Taken together, the results indicate a significant contribution by the TMS 10--12 portion of the protein to the recognition and transport of @entity6023 and give evidence that the cytoplasmic region proximal to TMS 6 also plays a role in @entity3907 interactions with P-glycoproteins. Interestingly, mutations within TMS 6 and 12 were found to cause a partial loss of @entity7358 inhibitor activity, suggesting that these regions participate in the interactions with @entity205 and its derivatives.

The use of a novel @entity3907 -based P-glycoprotein inhibitor to identify mutations that alter the interaction of the protein with XXXX .

@entity5808 :: ('MESH:D011691', 'Chemical') :: ['puromycin'] @entity70127 :: ('p|SUB|I|862|F', 'ProteinMutation') :: ['I862F'] @entity6023 :: ('MESH:D043823', 'Chemical') :: ['taxanes'] @entity21651 :: ('18669(Tax:10090)', 'Gene') :: ['mdr1b'] @entity19 :: ('10090', 'Species') :: ['Murine'] @entity1311 :: ('MESH:D017239', 'Chemical') :: ['paclitaxel'] @entity3907 :: ('MESH:C080625', 'Chemical') :: ['taxane'] @entity70131 :: ('p|SUB|N|988|D', 'ProteinMutation') :: ['N988D'] @entity205 :: ('MESH:D016572', 'Chemical') :: ['cyclosporin'] @entity70125 :: ('MESH:C429967', 'Chemical') :: ['tRA-96023', 'SB-RA-31012'] @entity70126 :: ('p|SUB|N|350|I', 'ProteinMutation') :: ['N350I'] @entity70130 :: ('c|SUB|A|933|T', 'DNAMutation') :: ['A933T'] @entity3812 :: ('MESH:D003078', 'Chemical') :: ['colchicine'] @entity7358 :: ('MESH:C070272', 'Chemical') :: ['PSC-833'] @entity70129 :: ('p|SUB|L|868|W', 'ProteinMutation') :: ['L868W'] @entity70128 :: ('p|SUB|L|865|F', 'ProteinMutation') :: ['L865F']
@entity1311 :: (MESH:D017239,Chemical) :: ['paclitaxel']
