Intramolecular Disulfide Bond Is a Critical Check Point Determining Degradative Fates of ATP-binding Cassette (ABC) Transporter ABCG2 Protein

Wakabayashi, Kunihiko; Nakagawa, Hiroshi; Tamura, Ai; Koshiba, S.; Hoshijima, Kazuyuki; Komada, Masayuki; Ishikawa, Toshihisa

doi:10.1074/jbc.c700133200

Cited by 76 publications

(100 citation statements)

References 27 publications

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“…Trafficking patterns for plasma membrane proteins to lysosomes or proteasomes may be altered under diverse conditions, including oxidative stress [glucose transporter GLUT1 (Fernandes et al, 2011) (Wakabayashi et al, 2007)]. While the mechanisms mediating these changes likely differ, there are similarities between our observations with CHT and effects of oxidative stress on GLUT1.…”

supporting

confidence: 40%

Peroxynitrite Donor SIN-1 Alters High-Affinity Choline Transporter Activity by Modifying Its Intracellular Trafficking

Cuddy¹,

Gordon²,

Black³

et al. 2012

J. Neurosci.

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Sodium-coupled, high-affinity choline transporters (CHTs) are inhibited by 3-morpholinosydnonimine (SIN-1) [peroxynitrite (ONOO Ϫ ) donor]; ONOOϪ can be produced from nitric oxide and reactive oxygen species during neurodegeneration. SIN-1 rapidly increases CHT internalization from the cell surface, and this correlates with decreased choline uptake. This study addresses mechanisms by which SIN-1 inhibits CHT function in human neuronal SH-SY5Y cells. Thus, mutant L531A-CHT, which does not constitutively internalize into cells by a clathrin-mediated process, is resistant to SIN-1 effects. This suggests that CHT inhibition is not due to oxidative-nitrosative inactivation of the protein and that decreased levels of cell surface CHT in SIN-1-treated cells is related to alterations in its trafficking and subcellular disposition. Dominant-negative proteins AP180C and dynamin-K44A, which interfere with clathrin-mediated and dynamindependent endocytosis, respectively, attenuate CHT inhibition by SIN-1. CHT in both vehicle-and SIN-1-treated cells colocalizes with Rab7, Rab9, and Lamp-1 in late endosomes and lysosomes to a similar extent. Lysosome inhibitors increase choline uptake, suggesting that CHT proteins are normally degraded by lysosomes, and this is not altered by oxidative stress. Unexpectedly, inhibitors of proteasomes, but not lysosomes, attenuate SIN-1-mediated inhibition of choline uptake, indicating that proteasomal degradation plays a role in regulating CHT disposition in SIN-1-treated cells. SIN-1 treatment also enhances CHT ubiquitination. Thus, CHT inhibition in SIN-1-treated cells is mediated by proteasomal degradation, which differs from inhibitory mechanisms for some neurotransmitter transporters under similar conditions. Increased oxidative-nitrosative stress in the microenvironment of cholinergic nerve terminals would diminish cholinergic transmission by reducing choline availability for ACh synthesis.

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supporting

confidence: 40%

Peroxynitrite Donor SIN-1 Alters High-Affinity Choline Transporter Activity by Modifying Its Intracellular Trafficking

Cuddy¹,

Gordon²,

Black³

et al. 2012

J. Neurosci.

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“…One possibility is that imatinib may enhance the degradation rate of ABCG2 mRNA through activation of a pathway associated with lysosomal degradation. 16,17 This and other possible mechanisms are currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Gardner

Sparreboom²,

Verweij³

et al. 2008

Cancer Biology & Therapy

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This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.Purpose: Chronic imatinib exposure has been shown to result in upregulation of the ABCB1 (P-glycoprotein) and ABCG2 (BCRP) transporters in vitro, for which imatinib is a substrate. This finding, along a trend towards increasing imatinib clearance over time in patients, has resulted in the suggestion that pharmacokinetic resistance may be contributing to eventual treatment failure. Here, we sought to determine the effects of long-term imatinib exposure on apparent oral clearance and transporter expression in vivo.Results: Plasma and liver concentrations of imatinib did not change significantly (p > 0.1) over the course of treatment, suggesting that steady-state had been reached. There was no increase in Abcb1 or Abcg2 expression in liver samples, whereas expression of these transporters in intestinal samples was highly variable, and no increase was apparent.Methods: Male BALB/c mice were treated daily-times 5 with oral imatinib at a dose of 50 mg/kg for 4 consecutive weeks. Imatinib concentrations were measured in plasma and liver tissue prior to treatment and following each week of dosing. Western blotting of liver and intestinal tissue lysates was performed to assess expression of Abcb1 and Abcg2.Conclusions: Imatinib does not appear to cause upregulation of ABC transporters in the hepatic and intestinal compartments in mice. These data do not support the possibility that autoinduction contributes to the development of resistance to imatinib.

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“…The protein is believed to function minimally as a homodimer, although recent three-dimensional structural analysis indicates it may function as a tetrameric complex made up of homodimers (36). Several cysteine residues appear to be important for the dimerization of the functional protein (37,38). Functional ABCG2 acts on a wide range of substrates, which is a common feature of the MRP class of transporters (30).…”

Section: Discussionmentioning

confidence: 99%

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

Brechbuhl

Gould

Kachadourian

et al. 2010

Journal of Biological Chemistry

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Glutathione (GSH) transport is vital for maintenance of intracellular and extracellular redox balance. Only a few human proteins have been identified as transporters of GSH, glutathione disulfide (GSSG) and/or GSH conjugates (GS-X). Human epithelial MDA1586, A549, H1975, H460, HN4, and H157 cell lines were exposed to 2,5-dihydroxychalcone, which induces a GSH efflux response. A real-time gene superarray for 84 proteins found in families that have a known role in GSH, GSSG, and/or GS-X transport was employed to help identify potential GSH transporters. ABCG2 was identified as the only gene in the array that closely corresponded with the magnitude of 2,5-dihydroxychalcone (2,5-DHC)-induced GSH efflux. The role of human ABCG2 as a novel GSH transporter was verified in a Saccharomyces cerevisiae galactose-inducible gene expression system. Yeast expressing human ABCG2 had 2.5-fold more extracellular GSH compared with those not expressing ABCG2. GSH efflux in ABCG2-expressing yeast was abolished by the ABCG2 substrate methotrexate (10 M), indicating competitive inhibition. In contrast, 2,5-DHC treatment of ABCG2-expressing yeast increased extracellular GSH levels in a dose-dependent manner with a maximum 3.5-fold increase in GSH after 24 h. In addition, suppression of ABCG2 with short hairpin RNA or ABCG2 overexpression in human epithelial cells decreased or increased extracellular GSH levels, respectively. Our data indicate that ABCG2 is a novel GSH transporter.Glutathione (GSH) is a tripeptide (␥-glutamyl-cysteinyl-glycine) that is maintained at millimolar concentrations within the cell. It is important in many signaling processes, including cell proliferation, post-translational modification of proteins, immune responses, and apoptosis (1, 2). The importance of GSH in normal cell function as well as its role in disease states such as cancer, cystic fibrosis, Parkinson disease, AIDS, liver dysfunction, and a host of other maladies has been well documented (3-8). For the purpose of detoxification and to respond to extracellular oxidative stress, cells express membrane proteins capable of transporting GSH, glutathione disulfide (GSSG), and GSH conjugates (GS-X).2 Currently, there are only a handful of proteins identified as capable of transporting GSH across membranes.The first human protein identified as a GS-X and/or GSSG transporter was the ATP-binding cassette (ABC) protein ABCC1, first called the GSH S-conjugate pump and later identified as the multidrug resistance protein MRP1 (9 -11). Since the discovery of ABCC1 as a GSH transporter, five other ABC family members have been shown to transport GSH and/or GS-X, including ABCC2, ABCC3, ABCC4, ABCC5, and ABCC7 (12-17). GSH transport has also been linked to the organic anion transporting polypeptide protein family, a subfamily of the solute carrying (SLC) protein superfamily. The SLC superfamily also contains mitochondria-specific membrane proteins (SLC25) capable of transporting GSH (18).Numerous compounds stimulate GSH, GSSG, and GS-X efflux through the ABC protei...

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Intramolecular Disulfide Bond Is a Critical Check Point Determining Degradative Fates of ATP-binding Cassette (ABC) Transporter ABCG2 Protein

Cited by 76 publications

References 27 publications

Peroxynitrite Donor SIN-1 Alters High-Affinity Choline Transporter Activity by Modifying Its Intracellular Trafficking

Peroxynitrite Donor SIN-1 Alters High-Affinity Choline Transporter Activity by Modifying Its Intracellular Trafficking

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

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