N-glycosylation of ABC transporters is associated with functional activity in sandwich-cultured rat hepatocytes

Draheim, Viola; Reichel, Andreas; Moenning, Ursula

doi:10.1016/j.ejps.2010.06.005

Cited by 35 publications

(26 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although this modification did not affect BCRP function, it may be involved in expression of functional BCRP. N-glycosylation status was shown to be important for apical sorting in polarized cells such as hepatocytes[198]. We found that the proteasome is involved, at least in part, in the post-translational down-regulation of BCRP [128].…”

Section: Molecular Mechanisms For Bcrp Gene Expressionmentioning

confidence: 73%

Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression

Nakanishi¹,

Ross²

2012

Chin J Cancer

253

187

View full text Add to dashboard Cite

Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance (MDR) in diverse cancer cells. BCRP physiologically functions as a part of a self-defense mechanism for the organism; it enhances elimination of toxic xenobiotic substances and harmful agents in the gut and biliary tract, as well as through the blood-brain, placental, and possibly blood-testis barriers. BCRP recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and targeted small therapeutic molecules relatively new in clinical use. Thus, BCRP expression in cancer cells directly causes MDR by active efflux of anticancer drugs. Because BCRP is also known to be a stem cell marker, its expression in cancer cells could be a manifestation of metabolic and signaling pathways that confer multiple mechanisms of drug resistance, self-renewal (sternness), and invasiveness (aggressiveness), and thereby impart a poor prognosis. Therefore, blocking BCRP-mediated active efflux may provide a therapeutic benefit for cancers. Delineating the precise molecular mechanisms for BCRP gene expression may lead to identification of a novel molecular target to modulate BCRP-mediated MDR. Current evidence suggests that BCRP gene transcription is regulated by a number of trans-acting elements including hypoxia inducible factor 1α, estrogen receptor, and peroxisome proliferator-activated receptor. Furthermore, alternative promoter usage, demethylation of the BCRP promoter, and histone modification are likely associated with drug-induced BCRP overexpression in cancer cells. Finally, PI3K/AKT signaling may play a critical role in modulating BCRP function under a variety of conditions. These biological events seem involved in a complicated manner. Untangling the events would be an essential first step to developing a method to modulate BCRP function to aid patients with cancer. This review will present a synopsis of the impact of BCRP-mediated MDR in cancer cells, and the molecular mechanisms of acquired MDR currently postulated in a variety of human cancers.

show abstract

Section: Molecular Mechanisms For Bcrp Gene Expressionmentioning

confidence: 73%

Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression

Nakanishi¹,

Ross²

2012

Chin J Cancer

253

187

View full text Add to dashboard Cite

show abstract

“…Following immunoblotting, we observed that the band corresponding to the ∼100 kDa isoform that is absent in the proband represents the glycosylated form of the protein (Figure S4). Since glycosylation is an important post-translational modification crucial to the proper folding, stability, subcellular localization and/or even function of many lysosomal proteins, including ABC transporters [22], this finding suggests a loss-of-function of both the full- and half-transporters encoded by ABCA5 in CGHT.…”

Section: Resultsmentioning

confidence: 99%

Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

et al. 2014

View full text Add to dashboard Cite

Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth.

show abstract

“…51,52 It has also been reported that N-glycosylation of P-gp functions as an important signal for intracellular trafficking, rather than directly influencing the activity of P-gp. 53 Considering that radixin functions as a membranecytoskeletal linker, it may play a direct role in the activity of P-gp. Further research would be needed to clarify in detail the role of radixin in P-gp functions.…”

Section: Resultsmentioning

confidence: 99%

Effect of Knockdown of Ezrin, Radixin, and Moesin on P-Glycoprotein Function in HepG2 Cells

Kano

Wada

Morimoto

et al. 2011

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

N-glycosylation of ABC transporters is associated with functional activity in sandwich-cultured rat hepatocytes

Cited by 35 publications

References 41 publications

Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression

Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression

Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

Effect of Knockdown of Ezrin, Radixin, and Moesin on P-Glycoprotein Function in HepG2 Cells

Contact Info

Product

Resources

About