Transcriptional Control of the Multi-Drug Transporter ABCB1 by Transcription Factor Sp3 in Different Human Tissues

Abstract

The ATP-binding cassette (ABC) transporter ABCB1, encoded by the multidrug resistance gene MDR1, is expressed on brain microvascular endothelium and several types of epithelium, but not on endothelia outside the CNS. It is an essential component of the blood-brain barrier. The aim of this study was to identify cell-specific controls on the transcription of MDR1 in human brain endothelium. Reporter assays identified a region of 500 bp around the transcription start site that was optimally active in brain endothelium. Chromatin immunoprecipitation identified Sp3 and TFIID associated with this region and EMSA (electrophoretic mobility shift assays) confirmed that Sp3 binds preferentially to an Sp-target site (GC-box) on the MDR1 promoter in brain endothelium. This result contrasts with findings in other cell types and with the colon carcinoma line Caco-2, in which Sp1 preferentially associates with the MDR1 promoter. Differences in MDR1 transcriptional control between brain endothelium and Caco-2 could not be explained by the relative abundance of Sp1:Sp3 nor by the ratio of Sp3 variants, because activating variants of Sp3 were present in both cell types. However differential binding of other transcription factors was also detected in two additional upstream regions of the MDR1 promoter. Identification of cell-specific controls on the transcription of MDR1 indicates that it may be possible to modulate multi-drug resistance on tumours, while leaving the blood brain barrier intact.

Oestrogen‐related receptor alpha mediates chemotherapy resistance of osteosarcoma cells via regulation of ABCB1

“…We found that ERRα can bind with SP3 to regulate the transcription of ABCB1 in OS resistant cells. It has been reported that SP3 may recruit TFIID to the ABCB1 promoter by binding to the second activation domain of Sp3 . In our study, XCT‐790 suppressed transcription of ABCB1 was abolished in cells transfected with si‐SP3.…”

“…It has been suggested that SP3 can regulate the transcription of ABCB1 in various human tissues . We then investigated SP3 was involved in ERRα regulated transcription of ABCB1.…”

“…It has been suggested that SP3 can regulate the transcription of ABCB1 in various human tissues. 28 We then investigated SP3 was involved in ERRα regulated transcription of ABCB1. The results showed that ERRα can directly bind with SP3 in MG-63 cells, further, the binding between ERRα and SP3 was increased in MG-63/ Dox cells ( Figure 6A).…”

SP and KLF Transcription Factors in Digestive Physiology and Diseases

“…SP1 has been implicated in drug resistance, as it positively regulates the expression of ATP-binding cassette transporter (ABCB1), encoded by the multidrug resistance gene MDR1 in Caco2 cells 90 . Cancer stem cells mediate tumor growth, resistance to chemotherapy, and metastasis; high levels of SP1 expression by these colorectal cancer stem cells might contribute to colorectal tumor drug resistance 84 .…”

Resveratrol reverses P-glycoprotein-mediated multidrug resistance of U2OS/ADR cells by suppressing the activation of the NF-κB and p38 MAPK signaling pathways

“…Chemotherapy drugs, including adriamycin (ADR), methotrexate and cyclophosphamide, are also applied in patients with osteosarcoma to further kill osteosarcoma cells following amputation surgery (1)(2)(3). However, upon long-term exposure of the tumor cells to chemother apy drugs, the surface of the tumor cells may overexpress P-glycoprotein (P-gp), an adenosine triphosphate-dependent drug efflux pump encoded by the multidrug resistance protein 1 (MDR1) gene (5,6). Overexpressed P-gp can mediate the efflux of a large number of intracellular chemotherapy drugs, thus leading to a significant reduction in the intracellular drug concentration (7,8), which causes drug resistance of tumor cells.…”