Down-regulation of Na+/H+ Exchanger Regulatory Factor 1 Increases Expression and Function of Multidrug Resistance Protein 4
Bibliographic record
Abstract
Multidrug resistance protein 4 (MRP4; ABCC4) is a member of the ATP-binding cassette superfamily of membrane transport proteins and confers resistance to nucleoside and nucleotide analogues as well as camptothecin derivatives. MRP4 also mediates the transmembrane transport of several eicosanoids, conjugated estrogens, and cyclic AMP. The subcellular localization of MRP4 depends on the cell type in which it is expressed, but the molecular determinants responsible for trafficking of MRP4 to the plasma membrane are unknown. Here, we describe the interaction of Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) with MRP4 via the last four amino acids ((1322)ETAL(1325)) of the transporter. Down-regulation of NHERF1 by small interfering RNA (siRNA) in HeLa cells significantly increased MRP4 levels at the plasma membrane, suggesting that internalization of the transporter was inhibited. Increased plasma membrane MRP4 was accompanied by increased efflux function as reflected by reduced cellular accumulation of the MRP4 substrates 6-mercaptopurine and 9-[2-(phosphonylmethoxy)ethyl]-adenine. Furthermore, enhanced green fluorescent protein-tagged MRP4 was internalized in monensin-treated cells, and this internalization was markedly reduced after NHERF1 down-regulation by siRNA. Together, these data establish NHERF1 as a novel protein-binding partner of MRP4 that plays a significant role in the internalization and drug efflux function of this transporter.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".