Action of Transcription Factors in the Control of Transferrin Receptor Expression in Human Brain Endothelium

Holloway, Karen; Sade, Hadassah; Romero, Ignacio A.; Male, David

doi:10.1016/j.jmb.2006.10.071

Cited by 14 publications

(17 citation statements)

References 41 publications

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“…Previously we have found that both Sp1 and Sp3 can be detected in hCMEC/D3 by EMSA-supershift assay with a consensus Sp oligonucleotide probe. Moreover, the activity of Sp3 is higher in brain endothelium, than non-brain endothelium [9]. The different techniques, all indicate that Sp3 is strongly expressed in brain endothelium, although Sp1 is also present.…”

Section: Resultsmentioning

confidence: 90%

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

2012

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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.

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Section: Resultsmentioning

confidence: 90%

“…Brain endothelium expresses particularly high levels of Sp3 in comparison with lung and dermal endothelium [9]. Sp1 is the prototype of a large family of transcription factors which bind GC-rich segments [11], [12].…”

Section: Introductionmentioning

confidence: 99%

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

2012

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“…Regulation of the 24-hour rhythm in the expression of TfR1 gene by c-MYC Among these, c-MYC is a potent activator of TfR1 gene transcription in mice and humans, and the transactivation effect was elicited through binding to the CACGTG E-box located in the first intron region (18,19). In addition, CLOCK/ BMAL1 heterodimers also bind cooperatively to CACGTG E-box sequences and regulate the rhythmic expression of their target genes (2).…”

Section: Resultsmentioning

confidence: 99%

Circadian Rhythm of Transferrin Receptor 1 Gene Expression Controlled by c-Myc in Colon Cancer–Bearing Mice

et al. 2010

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The abundance of cell surface levels of transferrin receptor 1 (TfR1), which regulates the uptake of ironbound transferring, correlates with the rate of cell proliferation. Because TfR1 expression is higher in cancer cells than in normal cells, it offers a target for cancer therapy. In this study, we found that the expression of TfR1 in mouse colon cancer cells was affected by the circadian organization of the molecular clock. The core circadian oscillator is composed of an autoregulatory transcription-translation feedback loop, in which CLOCK and BMAL1 are positive regulators and the Period (Per), Cryptochrome (Cry), and Dec genes act as negative regulators. TfR1 in colon cancer-bearing mice exhibited a 24-hour rhythm in mRNA and protein levels. Luciferase reporter analysis and chromatin immunoprecipitation experiments suggested that the clock-controlled gene c-MYC rhythmically activated the transcription of the TfR1 gene. Platinum incorporation into tumor DNA and the antitumor efficacy of transferrin-conjugated liposome-delivered oxaliplatin could be enhanced by drug administration at times when TfR1 expression increased. Our findings suggest that the 24-hour rhythm of TfR1 expression may form an important aspect of strategies for TfR1-targeted cancer therapy. Cancer Res; 70(15); 6238-46. ©2010 AACR.

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“…20,21 In addition to the indirect regulation that YY1 has for claudin expression through YY1’s up-regulation of Snail, 20,21 a direct relationship between YY1 and claudin expression has been reported by Holloway et al 58 These investigators demonstrated that the promoter regions of claudin-5 retain specific target sites for the Sp-family transcription factors TFIID and YY1, suggesting that YY1 could regulate claudin expression directly. The 5′ promoter of claudin-5 was also found to contain GC-rich segments with common sequence motifs, suggesting that this gene is regularly acted upon by common transcriptional factors such as YY1.…”

Section: Putative Direct Regulation Of Emt Gene Products By Yy1: mentioning

confidence: 94%

Targeting the Overexpressed YY1 in Cancer Inhibits EMT and Metastasis

Cho

Bonavida

2017

Crit Rev Oncog

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There have been recent developments in the treatment of various cancers, in particular non-metastatic cancers. However, many of the responding patients often relapse initially through the development of spread micro-and macro-metastases. Unfortunately, there are very few therapeutic modalities for the treatment of metastatic cancers. The development of cancer metastasis has been proposed to involve the epithelial–mesenchymal transition (EMT), in which the tumor cells with the EMT phenotype exhibit various phenotypic markers and molecular modifications that are manifested to resist most conventional therapies. YY1 is a target of the hyperactivated nuclear factor-kappa beta pathway in cancer and it was reported that YY1 also regulates cell survival and cell proliferation in addition to its role in EMT and resistance. The overexpression of YY1 in the majority of cancers has been correlated with poor prognosis. It is hypothesized that targeting YY1 may result in several anti-tumor activities, including inhibition of cell survival and cell proliferation, inhibition of EMT, and reversal of resistance. This review discusses the potential therapeutic targeting of an overexpressed transcription factor, Yin Yang 1 (YY1), which has been implicated in the development of EMT and drug resistance. Several examples targeting YY1 in experimental models are presented.

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Action of Transcription Factors in the Control of Transferrin Receptor Expression in Human Brain Endothelium

Cited by 14 publications

References 41 publications

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

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

Circadian Rhythm of Transferrin Receptor 1 Gene Expression Controlled by c-Myc in Colon Cancer–Bearing Mice

Targeting the Overexpressed YY1 in Cancer Inhibits EMT and Metastasis

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