Group leader: Dr. Andras Varadi
Following the cloning of the first cancer multidrug-resistance ABC-transporter, MDR1/P-glycoprotein in the late eighties, there was a boom in ABC-protein research. The field is progressing quickly, and there are some 500-1000 papers on ABC transporters every year. With the completion of the Human Genome Project, forty-eight genes encoding ABC-proteins were identified, many of which are associated with genetic disorders. Our group joined the international scene in the early nineties, working in close collaboration with the research group of Balázs Sarkadi. To date, after 15 years of continued excellence, we have established ourselves as one of the leading laboratories in the field. The two laboratories have established the “Budapest School of ABC-research”, and our 50 papers on ABC transporters, published in high-profile international journals testify our productivity. This success was honored by the Hungarian Academy of Sciences with the “Academy Award” in 2003. In 2006 our group has been invited for writing a review about ABC transporters for the highly prestigious journal, the Physiological Reviews. In addition to the traditional structure-function studies of transport proteins our group initiated a research project focusing on the expressional regulation of ABC transporter genes. Our work has also important physiological relevance since three of the ABC transporters studied in our laboratory are related to rare genetic disorders: that of pseudoxanthoma elasticum and sitosterolemia.
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The ABCC/MRP subfamily
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Numerous xenobiotics are eliminated from the cells by the sequence of oxidation, conjugation to an anionic group (glutathione, glucuronate or sulfate) and transport across the plasma membrane into the extracellular space. These transport processes are mediated by specific transport proteins, by multidrug resistance proteins (MRPs). MRPs contribute to drug resistance in cancer cells that is the major obstacle of successful chemotherapy. Up to now, nine members of the human MRP subfamily have been identified, they are members of the ATP-binding cassette (ABC) superfamily. Our aim is to study the function, the structure and the molecular mechanism of human MRP proteins.
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Genetic diseases and ABC-genes: pseudoxanthoma elasticum and sitosterolemia
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ABC-genes have been identified in each genomes that has been sequenced so far; in human the ABC-gene family is composed of 48 members (protein coding genes) and some “additional” members (pseudogenes). The high number of ABC-genes demonstrates their important, however mostly unknown, physiological role. According to the current hypothesis, different members have a wide expression pattern and partly overlapping functions, which account for the relatively complex phenotypes upon their loss of function.
We have embarked upon a research program that involves a wide spectrum of experimental strategies aimed to elucidate the molecular basis of pseudoxanthoma elasticum and sitosterolemia. Both diseases are caused by mutations in ABC-transporter genes: that of ABCC6 and ABCG5/G8, respectively. Investigating the molecular basis of monogenic inherited diseases provides invaluable information about normal human physiology. Such basic research usually does not result in therapeutic interventions directly but may open new avenues in such directions.
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Transcriptional regulation and evolution of human ABCC6 gene
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Mutations in the human ABCC6 gene lead to the development of pseudoxanthoma elasticum (PXE), a recessive disorder. The gene encodes a member of unknown physiological function of the large ABC transporter family. The gene is an interesting target to be studied for several reasons:
- ABCC6 is characterized by tissue-specific expression and PXE symptoms are present only in tissues with low or undetectable expression level;
- Secondary PXE is developed in various hemoglobinopathies, most frequently in beta-thalassemia;
- ABCC6 mutation carriers (approximately 1% of the population) may have higher risk to develop cardiovascular diseases than non-carriers;
- There is an important amount of data on the sequence variability of the gene, due to an international effort to diagnose PXE, which is the basis of genotype/phenotype relationship studies;
- ABCC6 has two human specific pseudogenes, which share 99% sequence identity with the disease-causing gene.
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