ArticleThe Journal of biological chemistry2011
Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 159 citations in OpenAlex.
- Transmembrane Transport of cAMP and AMP Using a Two Component Small Molecule Transport System.Angewandte Chemie (International ed. in English) · 2026Article
- ABCG8‑mediated sterol efflux increases cancer cell progression via the LRP6/Wnt/β‑catenin signaling pathway in radiotherapy‑resistant MDA‑MB‑231 triple‑negative breast cancer cells.International journal of molecular medicine · 2025Article
- Structural basis of human ABCC4 recognition of cAMP and ligand recognition flexibility.Cell & bioscience · 2025Article
- The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy.Frontiers in immunology · 2025Review
- The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects.International journal of molecular sciences · 2024Review
- ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling.British journal of cancer · 2024Article
- Structural basis of prostaglandin efflux by MRP4.Nature structural & molecular biology · 2024Article
- The xenobiotic transporterFrontiers in pharmacology · 2024Article
- Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes.Journal of physiology and biochemistry · 2023Review
- Structural insights into human ABCC4-mediated transport of platelet agonist and antagonist.Nature cardiovascular research · 2023Article
- The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance.International journal of molecular sciences · 2022Review
- Controlled variable selection in Weibull mixture cure models for high-dimensional data.Statistics in medicine · 2022Article
- Specific inhibition of the transporter MRP4/ABCC4 affects multiple signaling pathways and thrombus formation in human platelets.Haematologica · 2022Article
- Article
- Specific MRP4 Inhibitor Ceefourin-1 Enhances Apoptosis Induced by 6-Mercaptopurine in Jurkat Leukemic Cells, but Not in Normal Lymphoblast Cell Line CRL-1991.Medicina (Kaunas, Lithuania) · 2022Article
- Cyclic Nucleotide (cNMP) Analogues: Past, Present and Future.International journal of molecular sciences · 2021Review
- Histamine in cancer immunology and immunotherapy. Current status and new perspectives.Pharmacology research & perspectives · 2021Review
- Polymorphisms in the CYP2A6 and ABCC4 genes are associated with a protective effect on chronic myeloid leukemia in the Brazilian Amazon population.Molecular genetics & genomic medicine · 2021Article
- Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy.International journal of molecular sciences · 2021Article
- Regulation of MRP4 Expression by circHIPK3 via Sponging miR-124-3p/miR-4524-5p in Hepatocellular Carcinoma.Biomedicines · 2021Article
19 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Increased intracellular cAMP concentration plays a well established role in leukemic cell maturation. We previously reported that U937 cells stimulated by H2 receptor agonists, despite a robust increase in cAMP, fail to mature because of rapid H2 receptor desensitization and phosphodiesterase (PDE) activation. Here we show that intracellular cAMP levels not only in U937 cells but also in other acute myeloid leukemia cell lines are also regulated by multidrug resistance-associated proteins (MRPs), particularly MRP4. U937, HL-60, and KG-1a cells, exposed to amthamine (H2-receptor agonist), augmented intracellular cAMP concentration with a concomitant increase in the efflux. Extrusion of cAMP was ATP-dependent and probenecid-sensitive, supporting that the transport was MRP-mediated. Cells exposed to amthamine and the PDE4 inhibitor showed enhanced cAMP extrusion, but this response was inhibited by MRP blockade. Amthamine stimulation, combined with PDE4 and MRP inhibition, induced maximal cell arrest proliferation. Knockdown strategy by shRNA revealed that this process was mediated by MRP4. Furthermore, blockade by probenecid or MRP4 knockdown showed that increased intracellular cAMP levels induce maturation in U937 cells. These findings confirm the key role of intracellular cAMP levels in leukemic cell maturation and provide the first evidence that MRP4 may represent a new potential target for leukemia differentiation therapy.
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