tailieunhanh - Báo cáo Y học: Effects of ATP depletion and phosphate analogues on P-glycoprotein conformation in live cells

P-glycoprotein (Pgp), a membrane pump often responsible for the multidrug resistance of cancer cells, undergoes conformational changes in the presence of substrates/modulators, or upon ATP depletion, reflected by its enhanced reactivity with the UIC2 monoclonal antibody. When the UIC2-shift was elicited by certain modulators (. cyclosporin A or vinblastine, but not with verapamil or Tween 80), the subsequent binding of other monoclonal anti-Pgp Ig sharing epitopes with UIC2 (. ) was abolished [Nagy, H., Goda, K., Arceci, R., Cianfriglia, M., ´ Mechetner, E. & Szabo Jr, G. (2001) Eur. J. Biochem. 268, 2416–2420]. To further study the relationship between UIC2-shift. | Eur. J. Biochem. 269 2672-2677 2002 FEBS 2002 doi Effects of ATP depletion and phosphate analogues on P-glycoprotein conformation in live cells Katalin Goda1 Henrietta Nagy1 Eugene Mechetner2 Maurizio Cianfriglia3 and Gabor Szabo Jr1 1 Department of Biophysics and Cell Biology University of Debrecen Hungary 2Chemicon International Inc. Temecula CA USA 3Laboratorio di Immunologia Istituto Superiore di Sanita Rome Italy P-glycoprotein Pgp a membrane pump often responsible for the multidrug resistance of cancer cells undergoes conformational changes in the presence of substrates modula-tors or upon ATP depletion reflected by its enhanced reactivity with the UIC2 monoclonal antibody. When the UIC2-shift was elicited by certain modulators . cyclosporin A or vinblastine but not with verapamil or Tween 80 the subsequent binding of other monoclonal anti-Pgp Ig sharing epitopes with UIC2 . was abolished Nagy H. Goda K. Arceci R. Cianfriglia M. Mechetner E. Szabo Jr G. 2001 Eur. J. Biochem. 268 2416-2420 . To further study the relationship between UIC2-shift and the suppression of binding we compared on live cells how ATP depletion and treatment of cells with phosphate analogues sodium orthovanadate beryllium fluoride and fluoro-aluminate that trap nucleotides at the catalytic site affect the two phenomena. Similarly to modulators or ATP depleting agents all the phosphate analogues increased daunorubicin accumulation in Pgp- expressing cells. Prelabeling of ATP depleted cells with UIC2 completely abolished the subsequent binding of in accordance with the enhanced binding of the first mAb. Vanadate and beryllium fluoride but not fluoro-aluminate reversed the effect of cyclosporin A preventing UIC2 binding and allowing for labeling of cells with . Thus changes in UIC2 reactivity are accompanied by complementary changes in binding also in response to direct modulation of the ATP-binding site .

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