Matrimonios en peligro

Dóra SZEGŐ / staff scientist Nóra KUCSMA / staff scientist Katalin KISS / Phd student Dóra TÜRK / Phd student

Zsuzsanna SEBESTYÉN / technician

1. Development of compounds targeting

multidrug resistant cancer

despite considerable advances in drug discovery, resistance to chemotherapy confounds the effective treatment of patients. cancer cells can become re- sistant to a single drug or they may acquire broad cross-resistance to mechanistically and structurally unrelated drugs (multidrug resistance (mdr)). atP- binding cassette (aBc) proteins, present in most living organisms from prokaryotes to mammals, include the best known mediators of mdr. In par- ticular, mdr pumps aBcB1 (mdr1-Pgp), aBcc1- mrP1, and aBcG2-mXr actively extrude many types of drugs from cancer cells, thereby conferring resistance to those agents. Known substrates of Pgp include natural-product antineoplastics such as an- thracyclines, vinca alkaloids, taxanes, and epipodo- phyllotoxins. Pgp expression, frequently detected in human solid and hematological cancers, is a marker of chemoresistance or decreased survival in leukemi- as, lymphomas, osteosarcomas, small cell lung can-

from this observation is that mdr1-inverse com- pounds, whose toxicity is potentiated, rather than antagonized by the activity of Pgp, might provide an entirely novel way to fight multidrug resistant can- cer.

Preliminary data indicate that increased sensitiv- ity of otherwise multidrug resistant cells is not due to nonspecific factors arising during the selection of the cells. rather, toxicity of such “mdr1-inverse” com- pounds is directly enhanced by Pgp function. our general aim is to further characterize mdr1-inverse compounds showing increased toxicity in cells that are otherwise notoriously resistant to treatment. our objective is three-fold: 1) to identify further mdr1- inverse compounds; 2) to understand molecular mechanisms causing hypersensitivity of mdr cells and 3) to determine if and how these compounds can be used to overcome clinical Pgp-mediated multid- rug resistance.

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2. Study of the mitochondrial ABC transporter

protein ABCB6

aBc transporter proteins are located in the plasma membrane of the cells, or in the membranes of dif- ferent cellular organelles, and mediate the transloca- tion of various molecules across these barriers. some aBc proteins facilitate the transport of inorganic ions, whereas others pump organic compounds, in- cluding lipids, bile acids, glutathione and glucuronide conjugates, or even short peptides. most aBc proteins utilize the energy of atP hydrolysis for this transport activity (active transporters), but some aBc trans- porters form specific membrane channels. Their func- tional significance is suggested by the observation that they form one of the largest protein families. Based on sequence homology, 48 different aBc transport- ers (grouped into seven subfamilies ranging from a to G) have been defined in the human genome. our overall goal is to understand the pathophysiology of mitochondrial aBc transporters. In particular, we are interested in the role of aBcB6 in protecting the cells against xenobiotic toxicity.

aBcB6 belongs to the B [mdr/taP] sub-family of atP-binding cassette transporters. The B subfamily consists of 11 members, with functions ranging from peptide transport (aBcB2-3) to secretion of bile ac- ids (aBcB11). aBcB1-mdr1, the first human aBc transporter cloned and characterized through its ability to confer an mdr phenotype to cancer cells, stands out among aBc transporters by conferring the highest resistance against the greatest variety of com- pounds. In addition to the four full-length transport- ers, the aBcB subfamily contains seven half trans- porters, of which four (aBcB6, aBcB7, aBcB8 and

aBcB10) are believed to reside in the mitochondria. The function of the human mitochondrial aBc pro- teins is unknown. The outer membrane of mamma- lian mitochondria is freely permeable to most small molecules, whereas the inner membrane forms an impermeable barrier between the mitochondrial ma- trix and the cytosol. Based on the general role of aBc transporters, members expressed in the mitochondria are likely to play a role in transport processes through the inner membrane (thus regulating the intramito- chondrial milieu), or in the communication of signals transmitted from the mitochondria to the rest of the cell. although sequence conservation alone does not allow the exact determination of function, possible roles of mitochondrial aBc transporters include the export of toxic substances that accumulate in the mi- tochondrial matrix (cf. aBcB1), export of peptides (cf. aBcB2-3) or transport of phospholipids (cf. aBcB4). furthermore, depending on their orientation in the membrane, aBc transporters may also be involved in the import of certain constituents.

our general aim is to establish a comprehensive experimental system combining biochemical, ge- netic and cell biological approaches that will lead to the identification of the function and structure of mi- tochondrial aBc transporters and the nature of the compounds they transport. our studies are designed to address the following critical questions: first, what substrate(s) does aBcB6 transport? second, where is aBcB6 located in the cell? Third, what is the function- al form of aBcB6? candidate multidrug transporter?

Contact: [email protected]

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InTRInsICallY DIsoRDeReD pRoTeIns GRoUp

The group studies the structure-function relationship of intrinsically disordered proteins (IDPs) by a variety of techniques including bioinformatics, molecular biology, cell biology and structural biology. Our aim is to arrive at general conclusions through studies of selected IDPs, such as the plant stress protein ERD14 and human cell-cycle regulatory protein securin.