Download Gene Section ABCB1 (ATP-binding cassette, sub-family B (MDR/TAP), member 1)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
ABCB1 (ATP-binding cassette, sub-family B
(MDR/TAP), member 1)
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex
04, France
Published in Atlas Database: March 1998
Online updated version: http://AtlasGeneticsOncology.org/Genes/PGY1ID105.html
DOI: 10.4267/2042/37409
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1998 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Mainly at the cell membrane, with a secondary
localisation at the Golgi apparatus.
Other names: MDR1 (multidrug resistance 1)
Location: 7q21.2
Function
DNA/RNA
The P-glycoprotein is an energy-dependent efflux
pump involved in extrusion of many types of lypophilic
coumpounds; it may acts in normal tissues as a
protective mechanism against noxious xenobiotics and
as a transporter of endogenous substrates; in tumour
cells, the drug efflux pump results in a decrease in
intracellular drug concentration.
Description
Spans on a 120 kb genomic fragment; separated from
MDR3 gene (which is transcribed in the same
direction) by only 34 kb of intergenic DNA.
Transcription
Homology
5 kb mRNA.
Closely related gene to MDR3 (also called PGY3),
located at the same chromosomal site but not
implicated in multidrug resistance; there are 3 murine
homolog genes (mdr1, mdr2, mdr3) out of which only
2 (mdr1 and mdr3) are involved in multidrug
resistance; member of a large superfamily of
transmembrane transporter proteins named ATP
Binding Cassette (ABC) transporters or Traffic
ATPases; structural homology with other ABC
transporter proteins (CFTR, MRP).
Protein
Description
The protein is called P-glycoprotein; 170 kDa
transmembrane glycoprotein which includes 10-15 kDa
of N-term glycosylation; the N-term half of the
molecule contains 6 transmembrane domains, followed
by a large cytoplasmic domain with an ATP binding
site, and then a second section with 6 transmembrane
domains and an ATP binding site which shows over
65% of amino acid similarity with the first half of the
polypeptide.
Implicated in
Tumour cells resistance
Expression
Disease
Tumour cells resistance to a wide variety of
antineoplasic agents: doxorubicin, daunorubicin,
vinblastine, vincristine, colchicine, actinomycine D,
etoposide,
tenoposide,
mitoxantrone,
homoharringtonine; this phenomenon is named
'multidrug resistance' (MDR); P-glycoprotein is the
main protein responsible for the MDR phenotype;
Normally expressed at secretory surface of a number of
tissues, including biliary canaliculi, proximal tubules of
the kidney, intestinal and colonic epithelium;
hematopoietic stem cells express high levels of Pglycoprotein; overexpressed in many multidrug
resistant cell lines and in tumour cells resistant to
chemotherapy.
Atlas Genet Cytogenet Oncol Haematol. 1998;2(2)
45
ABCB1 (ATP-binding cassette, sub-family B (MDR/TAP), member 1)
Viguié F
selected KB carcinoma cells. Mol Biol Cell 1992 May;3(5):50720.
however, other agents may be involved in MDR,
independently or in association with P-glycoprotein:
"multidrug resistant associated protein" (MRP), "lung
resistance protein" (LRP), 'anthracycline associated
resistance protein" (ARX).
Simon SM, Schindler M. Cell biological mechanisms of
multidrug resistance in tumors. Proc Natl Acad Sci USA 1994
Apr 26;91(9):3497-504.
Torigoe K, Sato S, Kusaba H, Kohno K, Kuwano M, Okumura
K, Green ED, Tsui LC, Scherer SW, Schlessinger D, et al. A
YAC-based contig of 1.5 Mb spanning the human multidrug
resistance gene region and delineating the amplification unit in
three human multidrug-resistant cell lines. Genome Res 1995
Oct;5(3):233-44.
Leukemias
Disease
In leukemia, MDR1 overexpression is observed in
patients with a lower complete remission rate and with
a shortening of overall survival; frequently associated
with intermediate and poor prognosis karyotype; in
ANLL, approximately 50% of patients are MDR
positive at diagnosis (range 22-70%) and the MDR
phenotype is more frequently observed in CD34+
leukemias; in ALL, the average number of MDRpositive cases is 22% at diagnosis.
Bosch I, Croop J. P-glycoprotein multidrug resistance and
cancer. Biochim Biophys Acta 1996 Oct 9;1288(2):F37-54.
Gottesman MM, Pastan I, Ambudkar SV. P-glycoprotein and
multidrug resistance. Curr Opin Genet Dev 1996 Oct;6(5):6107.
Hegewisch-Becker S, Hossfeld DK. The MDR phenotype in
hematologic malignancies: prognostic relevance and future
perspectives. Ann Hematol 1996 Mar;72(3):105-17.
Srivastava RK, Srivastava AR, Cho-Chung YS. Multidrug
resistance in cancer. Int J Oncol 1996:9:879-84. (Review)
Tumour cell lines
Zhou DC, Ramond S, Viguie F, Faussat AM, Zittoun R, Marie
JP. Sequential emergence of MRP- and MDR1-gene overexpression as well as MDR1-gene translocation in
homoharringtonine-selected K562 human leukemia cell lines.
Int J Cancer 1996 Jan 26;65(3):365-71.
Note
In numerous continuous tumour cell lines which
acquired experimentally a MDR phenotype when
cultured
with
progressively increasing
drug
concentration, the acquisition of MDR was associated
with hyperexpression of P-glycoprotein; for the higher
levels of expression, southern blots revealed an
increase in the number of copies of the MDR1 gene per
cell.
Cytogenetics
The genomic amplification of MDR1 appears as
extrachromosomic 'double-minute chromosomes' (DM)
or intrachromosomic 'homogeneous staining regions'
(HSR).
Oncogenesis
Amplification.
Hunault M, Zhou D, Delmer A, Ramond S, Viguié F, Cadiou M,
Perrot JY, Levy V, Rio B, Cymbalista F, Zittoun R, Marie JP.
Multidrug resistance gene expression in acute myeloid
leukemia: major prognosis significance for in vivo drug
resistance to induction treatment. Ann Hematol 1997
Feb;74(2):65-71.
Martínez A, San Miguel JF, Valverde B, Bárez A, Moro MJ,
García-Marcos MA, Pérez-Simón JA, Vidriales B, Orfao A.
Functional expression of MDR-1 in acute myeloid leukemia:
correlation with the clinical-biological, immunophenotypical,
and prognostic disease characteristics. Ann Hematol 1997
Sep;75(3):81-6.
van den Heuvel-Eibrink MM, van der Holt B, te Boekhorst PA,
Pieters R, Schoester M, Löwenberg B, Sonneveld P. MDR 1
expression is an independent prognostic factor for response
and survival in de novo acute myeloid leukaemia. Br J
Haematol 1997 Oct;99(1):76-83.
References
Ruiz JC, Choi KH, von Hoff DD, Robinson IB, Wahl GM.
Autonomously replicating episomes contain mdr1 genes in a
multidrug-resistant human cell line. Mol Cell Biol 1989
Jan;9(1):109-15.
Willman CL. The prognostic significance of the expression and
function of multidrug resistance transporter proteins in acute
myeloid leukemia: studies of the Southwest Oncology Group
Leukemia Research Program. Semin Hematol 1997 Oct;34(4
Suppl 5):25-33.
Baer MR, Bloomfield CD. Multidrug resistance in acute myeloid
leukemia. J Natl Cancer Inst 1991 May 15;83(10):663-5.
This article should be referenced as such:
Trent JM, Callen DE. Molecular and Cellular Biology of
Multidrug Resistance in Tumor Cells (IM Roninson Ed.),
Plenum Publishing Corporation 1991; pp169.
Viguié F. ABCB1 (ATP-binding cassette, sub-family B
(MDR/TAP), member 1) Atlas Genet Cytogenet Oncol
Haematol.1998;2(2):45-46.
Schoenlein PV, Shen DW, Barrett JT, Pastan I, Gottesman
MM. Double minute chromosomes carrying the human
multidrug resistance 1 and 2 genes are generated from the
dimerization of submicroscopic circular DNAs in colchicine-
Atlas Genet Cytogenet Oncol Haematol. 1998;2(2)
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