Thesis supervisor: Tamás Orbán
Location of studies (in Hungarian): Semmelweis Egyetem Abbreviation of location of studies: SE
Description of the research topic:
Investigating the regulation of the human ABCG2 membrane transporter
(Research proposal, Semmelweis University, Doctoral School of Molecular Medicine)
The ABCG2 is a “multidrug transporter” protein that is believed to play a protective role in various cell types by exporting several toxic endobiotics and xenobiotics. Apart from liver, kidney or endometrial cells, the ABCG2 serves as an important “guardian” also in hematopoietic and embryonic stem cells. However, this function may have negative consequences in tumors, contributing to the “multidrug resistance” phenotype, severely lowering the efficiency of chemotherapies.
In the last couple of years, many naturally occurring variants of the protein have been characterized, helping to elucidate various aspects of the transporter function. Among them, by using a GFP-based fluorescent assay, our research team could provide evidence that the ABCG2 protein is able to recognize its substrates directly in the plasma membrane, and expel them from the cells [1, 2]. In addition to study the protein function, we started to investigate the expression regulation of the gene at the RNA-level, and could show the functional role of 5’ non-coding exons produced by different promoter variants in certain cell types, including stem cells [3]. Our results revealed that RNA-based regulatory processes play important roles in “fine-tuning” the transporter function, and help to understand the effect of many genetic variants [4].
Our current research aims at elucidating the detailed molecular mechanisms influencing the formation and function(s) of ABCG2 mRNA isoforms. To understand the roles of different promoters and the numerous mRNA variants, we plan to investigate the tissue specific regulation of sequence elements required for proper ABCG2 transcription, splicing and alternative splicing. We also aim at studying the stability of the mRNA isoforms: one important aspect is the regulation by different microRNAs, but we also focus on the recently described regulatory pathways of the so called circular-RNAs which may have important roles also in the case of ABCG2. Our studies are based on the several genetic variants we have identified during the recent years, and their potential roles and functions can be tested in stable mammalian expression systems established by transposon-based gene delivery methods. Using the ABCG2 membrane transporter gene as a model, our research program could result in a better understanding of certain RNA-based regulatory pathways, but by investigating the roles of several naturally occurring variants, these studies may also contribute to a better and more efficient therapy of certain tumors.
Some relevant publications from our laboratory:
[1] T.I. Orban, L. Seres, C. Ozvegy-Laczka, N.B. Elkind, B. Sarkadi, L. Homolya, Combined localization and real-time functional studies using a GFP-tagged ABCG2 multidrug transporter, Biochem Biophys Res Commun, 367 (2008) 667-673.
[2] L. Homolya, T.I. Orban, L. Csanady, B. Sarkadi, Mitoxantrone is expelled by the ABCG2 multidrug transporter directly from the plasma membrane, Biochim Biophys Acta, 1808 (2011) 154-163.
[3] S. Sandor, T. Jordanidisz, A. Schamberger, G. Varady, Z. Erdei, A. Apati, B. Sarkadi, T.I. Orban, Functional characterization of the ABCG2 5' non-coding exon variants: Stem cell specificity, translation efficiency and the influence of drug selection, Biochim Biophys Acta, 1859 (2016) 943-951.
[4] B. Zambo, O. Mozner, Z. Bartos, G. Torok, G. Varady, A. Telbisz, L. Homolya, T.I. Orban, B. Sarkadi, Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter, Cell Mol Life Sci, 77 (2020) 365-378.
Deadline for application: 2024-06-30
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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