Increased P-glycoprotein messenger RNA stability in rat liver tumors in vivo

Lee, Chow Hwee; Bradley, Grace; Ling, Victor

doi:10.1002/(sici)1097-4652(199810)177:1<1::aid-jcp1>3.0.co;2-r

Cited by 41 publications

(10 citation statements)

References 44 publications

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“…Tissue-specific regulatory elements such as locus control regions might be located far upstream or downstream to the region with promoter activity in drug-resistant NCI/ADR-RES cells described here. 31 Equally, mRNA stability is known to regulate P-glycoprotein in both normal human tissues and drug-resistant lines, 22,32,33 and could result in the different tissue specific levels of MDR1 USP-derived transcripts.…”

Section: Discussioncontrasting

confidence: 53%

Production of P‐glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first‐line chemotherapy in advanced breast cancer

Raguz

Randle

Sharpe

et al. 2007

Intl Journal of Cancer

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Multidrug resistance, the phenomenon by which cells treated with a drug become resistant to the cytotoxic effect of a variety of other structurally and functionally unrelated drugs, is often associated with the expression of P-glycoprotein, an efflux membrane pump coded by the MDR1 (ABCB1) gene. Transcription from MDR1 can start at 2 promoters: a well-characterized downstream promoter and an as yet uncharacterized upstream promoter (USP). We have previously determined that the USP is activated in some drug-resistant cell lines, in primary breast tumors and in metastatic epithelial cells isolated from the lymph nodes of breast cancer patients. In this study, we report the cloning and characterization of the MDR1 USP and studied its association with chemotherapy response in breast cancer patients. Deletion analysis indicated that a nearby endogenous retroviral long terminal repeat is not responsible for promoter activation, and that the region within the first 400 nucleotides upstream from the transcription start point contained all the elements necessary for promoter activity in drug-resistant cells. We identified an element recognized by the transcription factor NF-IL6 (activated upon interleukin-6 exposure) which is necessary for promoter activity in drug-resistant cells and plays a role in the activation of the promoter in response to interleukin-6 in breast cancer MCF-7 cells. Although transcripts from this promoter are associated with translating polyribosomes, their low abundance makes the amount of synthesized P-glycoprotein insufficient to affect the response to first-line chemotherapy in patients with advanced breast cancer. ' 2007 Wiley-Liss, Inc.

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Section: Discussioncontrasting

confidence: 53%

Production of P‐glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first‐line chemotherapy in advanced breast cancer

Raguz

Randle

Sharpe

et al. 2007

Intl Journal of Cancer

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“…Although regulation due to changes in the MDR1 mRNA stability (19), P-glycoprotein turnover (20), or trafficking (21) have been suggested, transcriptional regulation is widely considered to be the key step accounting for the complex spatiotemporal pattern of expression in vivo (22,23). It has also generally been assumed that up-regulation of MDR1 mRNA leads to an increase in P-glycoprotein.…”

Section: Mdrmentioning

confidence: 99%

P-glycoprotein (MDR1) Expression in Leukemic Cells Is Regulated at Two Distinct Steps, mRNA Stabilization and Translational Initiation

Yagüe

Armesilla

Harrison

et al. 2003

Journal of Biological Chemistry

121

132

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Multidrug resistance in acute myeloid leukemia is often conferred by overexpression of P-glycoprotein, encoded by the MDR1 gene. We have characterized the key regulatory steps in the development of multidrug resistance in K562 myelogenous leukemic cells. Unexpectedly, up-regulation of MDR1 levels was not due to transcriptional activation but was achieved at two distinct posttranscriptional steps, mRNA turnover and translational regulation. The short-lived (half-life 1 h) MDR1 mRNA of naïve cells (not exposed to drugs) was stabilized (halflife greater than 10 h) following short-term drug exposure. However, this stabilized mRNA was not associated with translating polyribosomes and did not direct Pglycoprotein synthesis. Selection for drug resistance, by long-term exposure to drug, led to resistant lines in which the translational block was overcome such that the stabilized mRNA was translated and P-glycoprotein expressed. The absence of a correlation between steadystate MDR1 mRNA and P-glycoprotein levels was not restricted to K562 cells but was found in other lymphoid cell lines. These findings have implications for the avoidance or reversal of multidrug resistance in the clinic. MDR1 is the most common impediment to successful chemotherapy for a variety of cancers (1). The most frequent form of drug resistance in relapsed acute leukemia is overexpression of P-glycoprotein (2, 3). P-glycoprotein is a member of the ATPbinding cassette superfamily of active transporters and functions as an energy-dependent efflux pump that reduces the intracellular concentration of cytotoxic compounds and, hence, their toxicity. P-glycoprotein has a broad substrate specificity and can confer resistance to a wide range of different cytotoxic compounds (4).Most pre-clinical and clinical efforts to overcome MDR aim to modulate P-glycoprotein activity. However, clinical trials of compounds that inhibit P-glycoprotein activity have had limited success and led to adverse pharmacokinetic side effects (1). It may, therefore, be more appropriate to target MDR1 expression. Indeed, MDR1 transcription has been targeted with Ecteinascidin 743 in pre-clinical studies (5) and more recently by modulation of the nuclear receptor SXR (6). Strategies involving antisense and transcriptional decoy (7) and the use of anti-MDR1 mRNA hammerhead ribozymes have also been suggested (8).Stresses such as short-term exposure to cytotoxic drugs results in the up-regulation of MDR1 mRNA levels in many cell lines (9 -13) and in human metastatic sarcomas in vivo (14). This is frequently due to transcriptional activation of the MDR1 gene and has been reported in many cell lines after different physical and chemical stimulations and in cells selected for resistance to a variety of cytotoxic drugs (5,9,10,15,16). In cell lines selected for drug resistance, increased MDR1 gene expression is also the result of amplification of the MDR1 locus and the appearance of self-replicating episomes (4). Gene rearrangements that constitutively activate MDR1 transcription have also...

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“…Pgp1, Pgp2, and Pgp3 mRNAs have a higher half-life in rat tumor cells than in normal cells (15), whereas rat MDR hepatocytes in culture present a higher amount of PGP2 protein due to a post-transcriptional mechanism controlling mRNA stability (14). Human MDR1 mRNA has a half-life of 30 min, which is prolonged to more than 20 h upon treatment with cycloheximide, suggesting that protein synthesis inhibition may influence the stability of certain mRNAs (16,17).…”

mentioning

confidence: 99%

EhPgp5 mRNA Stability Is a Regulatory Event in theEntamoeba histolytica Multidrug Resistance Phenotype

López-Camarillo¹,

Luna-Arias²,

Marchat³

et al. 2003

Journal of Biological Chemistry

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The multidrug resistance (MDR) phenotype inEntamoeba histolytica, the protozoan parasite responsible for human amoebiasis, presents the multidrug resistance (MDR) 1 phenotype (1) described first in mammalian cells (2) and then in several protozoan parasites (3, 4). MDR is associated with the overexpression of a 170-kDa membrane molecule known as P-glycoprotein (PGP), an energy-dependent pump that extrudes drugs from the cells (5, 6). In E. histolytica, MDR phenotype is given mainly by overexpression of the EhPgp1 and EhPgp5 genes, which are finely regulated by transcriptional factors (7-9). Although EhPgp1 is constitutively expressed in drug-resistant trophozoites of clone C2, EhPgp5 gene is overexpressed only when C2 cells are grown in a high emetine concentration (10, 11). Both genes are also amplified in the presence of a high drug concentration (12).Transcriptional regulation of eukaryotic mdr genes has been considered as the major control point for PGP synthesis, although gene amplification mechanisms also participate in this event (12, 13). Moreover, there is growing evidence of pivotal post-transcriptional (14 -17) and post-translational (18 -20) regulation of the PGP expression. On the other hand, mRNA stability has recently emerged as a critical control step in determining cellular stationary mRNA levels. The abundance of a particular mRNA can fluctuate many folds due to alterations in mRNA stability without any change in the transcription rate (21). The mRNA half-life is determined by a complex set of protein interactions at the 3Ј-untranslated region (3Ј-UTR) depending on conserved cis-element sequences and secondary structures (for review, see Ref. 22). The 3Ј-UTR also contains consensus sequence elements that mediate mRNA nuclear export, cytoplasmic localization, translation efficacy, and polyadenylation control (23, 24). The pre-mRNAs are polyadenylated in a reaction involving 3Ј endonucleolytic cleavage followed by poly(A) tail synthesis (25). Poly(A) tail is also a modulator of mRNA stability and translation (26,27). Strict control of poly(A) tail length is achieved by the concerted interplay of key factors, including poly(A) polymerase, deadenylases, and poly(A)-binding protein activities (25).Several reports have addressed the importance of mRNA stability on the mdr genes expression regulation. Pgp1, Pgp2, and Pgp3 mRNAs have a higher half-life in rat tumor cells than in normal cells (15), whereas rat MDR hepatocytes in culture present a higher amount of PGP2 protein due to a post-transcriptional mechanism controlling mRNA stability (14). Human MDR1 mRNA has a half-life of 30 min, which is prolonged to more than 20 h upon treatment with cycloheximide, suggesting that protein synthesis inhibition may influence the stability of certain mRNAs (16,17). However, molecular mechanisms controlling mdr mRNA stability remains to be elucidated.In E. histolytica, mRNA stability mechanisms have not been studied yet. The presence of higher levels of EhPGP5 protein in the multidrug-resistant trophozoites of c...

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Increased P-glycoprotein messenger RNA stability in rat liver tumors in vivo

Cited by 41 publications

References 44 publications

Production of P‐glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first‐line chemotherapy in advanced breast cancer

Production of P‐glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first‐line chemotherapy in advanced breast cancer

P-glycoprotein (MDR1) Expression in Leukemic Cells Is Regulated at Two Distinct Steps, mRNA Stabilization and Translational Initiation

EhPgp5 mRNA Stability Is a Regulatory Event in theEntamoeba histolytica Multidrug Resistance Phenotype

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