Az ABCG2 multidrog transzporter fehérje szerkezetének és működésének vizsgálata = Structure and function of the multidrug transporter ABCG2

Az ABCG2 multidrog transzporternek fontos szerepe van mind a daganatok kemoterapia-rezisztenciajaban, mind a fiziologias xenobiotikum transzportban. A projektben előallitottuk az ABCG2 feherje kulonboző mutans es polimorf valtozatait, elvegeztuk ezek reszletes funkcionalis vizsgalatat. Egy sejtfelszinen reagalo, konformacio-erzekeny anti-ABCG2 monoklonalis antitest alkalmazasaval felderitettuk a transzporter funkcionalis allapotait, kemiai modositasok es mutaciok segitsegevel elvegeztuk az epitopok jellemzeset es molekularis szintű modellezeset. Reszletesen elemeztuk az ABCG2 transzporter es a membran lipidek kolcsonhatasait, megallapitottuk a membran koleszterin jelentős szabalyozo szerepet. Az ABCG2 transzporter es celzott hatasu rakellenes vegyuletek kolcsonhatasainak vizsgalata soran klinikailag is alkalmazott gyogyszerekre vonatkozoan kaptunk uj informaciokat. Uj modszereket fejlesztettunk ki az ABCG2 szabalyozasanak, lokalizaciojanak es funkciojanak vizsgalatara, elemeztuk a transzporter expressziojat human embrionalis őssejtekben. Tobb, magas impakt faktoru nemzetkozi folyoiratban kozoltunk a temarol review cikkeket. | The human ABCG2 multidrug transporter plays a key role in the chemotherapy resistance of malignant tumors, as well as in the physiological elimination of xenobiotics. In this project we have prepared and expressed various mutant and polymorphic variants of the transporter, performed their detailed functional characterization. By using a cell-surface reacting, conformation-sensitive monoclonal antibody against ABCG2, we mapped the functional states of the transporter. In these experiments we applied specific chemical modifications and generated site-directed mutations to characterize the extracellular loop epitope region of ABCG2 and constructed a molecular model for this part of the transporter. We have investigated the modulation of ABCG2 by membrane lipids and found a major role for cholesterol in regulating the transport activity of this protein. By examining a number of new targeted anticancer agents we found that ABCG2 interacts with several of these compounds and may be involved in the resistance against clinically applied molecules. We have developed new methods for studying the regulation, localization and function of the ABCG2 protein, examined the expression profile of this transporter in human embryonic stem cells. During this project we have published several review articles in high-impact international journals.