TY  - JOUR
AU  - Zukić, Branka
AU  - Radmilović Milena
AU  - Stojiljković, Maja
AU  - Tošić, Nataša
AU  - Pourfarzad, Farzin
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Čolović, Nataša
AU  - Philipsen, Sjaak
AU  - Patrinos, George P.
AU  - Pavlović, Sonja
PY  - 2010
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/422
AB  - Aims: Thiopurine S-methyltransferase (TPMT) activity is polymorphic, and a trimodal distribution has been demonstrated in Caucasians (low, intermediate and high methylator groups). The TPMT gene promoter contains a variable number of three GC-rich tandem repeats, namely A, B and C, ranging from three to nine in length in a A(n)B(m),C architecture. Materials & methods: Here, we investigated the influence of number and type of TPMT gene promoter tandem repeats on human TPMT gene transcription in K562 cells transiently transfected with reporter constructs bearing various variable number of tandem repeats (VNTR) and addressed the interaction of transcription factor binding to the VNTRs by electrophoretic mobility shift assays. Results: We found that the distribution patterns of VNTR alleles do not significantly differ among acute lymphoblastic leukemia patients, acute myeloid leukemia patients and normal individuals. We also demonstrated that the A repeat has a negative effect in TPMT gene transcription and that a positive regulatory element, identified immediately upstream to the VNTR region of the TPMT gene promoter, is indispensable for TPMT gene transcription. Our electrophoretic mobility shift assay analysis indicated that the Sp1 and Sp3 transcription factors bind to the VNTR repeats. Conclusion: Overall, our data underline that both the number and type of VNTRs, as well as the upstream regulatory region of the TPMT gene promoter, determine the overall level of TPMT gene transcription. It remains to be seen whether these VNTRs can be employed as pharmacogenetic markers to individualize thiopurine therapy.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription
EP  - 557
IS  - 4
SP  - 547
VL  - 11
DO  - 10.2217/PGS.10.7
ER  - 

@article{
author = "Zukić, Branka and Radmilović Milena and Stojiljković, Maja and Tošić, Nataša and Pourfarzad, Farzin and Dokmanović, Lidija and Janić, Dragana and Čolović, Nataša and Philipsen, Sjaak and Patrinos, George P. and Pavlović, Sonja",
year = "2010",
abstract = "Aims: Thiopurine S-methyltransferase (TPMT) activity is polymorphic, and a trimodal distribution has been demonstrated in Caucasians (low, intermediate and high methylator groups). The TPMT gene promoter contains a variable number of three GC-rich tandem repeats, namely A, B and C, ranging from three to nine in length in a A(n)B(m),C architecture. Materials & methods: Here, we investigated the influence of number and type of TPMT gene promoter tandem repeats on human TPMT gene transcription in K562 cells transiently transfected with reporter constructs bearing various variable number of tandem repeats (VNTR) and addressed the interaction of transcription factor binding to the VNTRs by electrophoretic mobility shift assays. Results: We found that the distribution patterns of VNTR alleles do not significantly differ among acute lymphoblastic leukemia patients, acute myeloid leukemia patients and normal individuals. We also demonstrated that the A repeat has a negative effect in TPMT gene transcription and that a positive regulatory element, identified immediately upstream to the VNTR region of the TPMT gene promoter, is indispensable for TPMT gene transcription. Our electrophoretic mobility shift assay analysis indicated that the Sp1 and Sp3 transcription factors bind to the VNTR repeats. Conclusion: Overall, our data underline that both the number and type of VNTRs, as well as the upstream regulatory region of the TPMT gene promoter, determine the overall level of TPMT gene transcription. It remains to be seen whether these VNTRs can be employed as pharmacogenetic markers to individualize thiopurine therapy.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription",
pages = "557-547",
number = "4",
volume = "11",
doi = "10.2217/PGS.10.7"
}

Zukić, B., Radmilović Milena, Stojiljković, M., Tošić, N., Pourfarzad, F., Dokmanović, L., Janić, D., Čolović, N., Philipsen, S., Patrinos, G. P.,& Pavlović, S.. (2010). Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription. in Pharmacogenomics
Future Medicine Ltd, London., 11(4), 547-557.
https://doi.org/10.2217/PGS.10.7

Zukić B, Radmilović Milena, Stojiljković M, Tošić N, Pourfarzad F, Dokmanović L, Janić D, Čolović N, Philipsen S, Patrinos GP, Pavlović S. Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription. in Pharmacogenomics. 2010;11(4):547-557.
doi:10.2217/PGS.10.7 .

Zukić, Branka, Radmilović Milena, Stojiljković, Maja, Tošić, Nataša, Pourfarzad, Farzin, Dokmanović, Lidija, Janić, Dragana, Čolović, Nataša, Philipsen, Sjaak, Patrinos, George P., Pavlović, Sonja, "Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription" in Pharmacogenomics, 11, no. 4 (2010):547-557,
https://doi.org/10.2217/PGS.10.7 . .