NDA@SZTAKI

Functional characterization of the ABCG2 5' non-coding exon variants: Stem cell specificity, translation efficiency and the influence of drug selection.

SĂĄndor, SĂĄra Anna

Jordanidisz, T.

Schamberger, Anita

VĂĄrady, GyĂśrgy

Erdei, Zsuzsa

Apåti, Ágota

Sarkadi, BalĂĄzs

OrbĂĄn, TamĂĄs I.

Elsevier

2016

QH3015 Molecular biology / molekulĂĄris biolĂłgia

QH3020 Biophysics / biofizika

ABCG2 is a multidrug transporter with wide substrate specificity, and is believed to protect several cell types from various xenobiotics and endobiotics. This "guardian" function is important in numerous cell types and tissue barriers but becomes disadvantageous by being responsible for the multidrug resistance phenotype in certain tumor cells. ABCG2 regulation at the protein level has already been extensively studied, however, regulation at the mRNA level, especially the functional role of the various 5' untranslated exon variants (5' UTRs) has been elusive. In the present work, we describe a comprehensive characterization of four ABCG2 mRNA variants with different exon 1 sequences, investigate drug inducibility, stem cell specificity, mRNA stability, and translation efficiency. Although certain variants (E1B and E1C) are considered as "constitutive" mRNA isoforms, we show that chemotoxic drugs significantly alter the expression pattern of distinct ABCG2 mRNA isoforms. When examining human embryonic stem cell lines, we provide evidence that variant E1A has an expression pattern coupled to undifferentiated stem cell stage, as its transcript level is regulated parallel to mRNAs of Oct4 and Nanog pluripotency marker genes. When characterizing the four exon 1 variants we found no significant differences in terms of mRNA stabilities and half-lives of the isoforms. In contrast, variant E1U showed markedly lower translation efficiency both at the total protein level or regarding the functional presence in the plasma membrane. Taken together, these results indicate that the different 5' UTR variants play an important role in cell type specific regulation and fine tuning of ABCG2 expression.

angol

Article

PeerReviewed

info:eu-repo/semantics/article

text

http://real.mtak.hu/41881/1/2016_BBAGRM_G2_mRNA_Sari_ms.pdf

Såndor, Såra Anna and Jordanidisz, T. and Schamberger, Anita and Vårady, GyÜrgy and Erdei, Zsuzsa and Apåti, Ágota and Sarkadi, Balåzs and Orbån, Tamås I. (2016) Functional characterization of the ABCG2 5' non-coding exon variants: Stem cell specificity, translation efficiency and the influence of drug selection. BIOCHIMICA ET BIOPHYSICA ACTA, 2016. pp. 1-25. ISSN 0006-3002

http://real.mtak.hu/41881/

http://dx.doi.org/10.1016/j.bbagrm.2016.05.007

MTMT:3071715; doi:10.1016/j.bbagrm.2016.05.007