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4. Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins.

Author

Thévenod, Frank, Herbrechter, Robin, Schlabs, Carolin, Pethe, Abhishek, Wing-Kee Lee, Wolff, Natascha A., and Roussa, Eleni

Abstract

The transmembrane protein SLC22A17 [or the neutrophil gelatinase-associated lipocalin/lipocalin-2 (LCN2)/24p3 receptor] is an atypical member of the SLC22 family of organic anion and cation transporters: it does not carry typical substrates of SLC22 transporters but mediates receptor-mediated endocytosis (RME) of LCN2. One important task of the kidney is the prevention of urinary loss of proteins filtered by the glomerulus by bulk reabsorption of multiple ligands via megalin:cubilin:amnionless-mediated endocytosis in the proximal tubule (PT). Accordingly, overflow, glomerular, or PT damage, as in Fanconi syndrome, results in proteinuria. Strikingly, up to 20% of filtered proteins escape the PT under physiological conditions and are reabsorbed by the distal nephron. The renal distal tubule and collecting duct express SLC22A17, which mediates RME of filtered proteins that evade the PT but with limited capacity to prevent proteinuria under pathological conditions. The kidney also prevents excretion of filtered essential and nonessential transition metals, such as iron or cadmium, respectively, that are largely bound to proteins with high affinity, e.g., LCN2, transferrin, or metallothionein, or low affinity, e.g., microglobulins or albumin. Hence, increased uptake of transition metals may cause nephrotoxicity. Here, we assess the literature on SLC22A17 structure, topology, tissue distribution, regulation, and assumed functions, emphasizing renal SLC22A17, which has relevance for physiology, pathology, and nephrotoxicity due to the accumulation of proteins complexed with transition metals, e.g., cadmium or iron. Other putative renal functions of SLC22A17, such as its contribution to osmotic stress adaptation, protection against urinary tract infection, or renal carcinogenesis, are discussed. [ABSTRACT FROM AUTHOR]

Published
2023
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8. Dependence of ABCB1 transporter expression and function on distinct sphingolipids generated by ceramide synthases-2 and -6 in chemoresistant renal cancer

Author

Lee, Wing-Kee, primary, Maaß, Michelle, additional, Quach, Amy, additional, Poscic, Nataliya, additional, Prangley, Holly, additional, Pallott, Erin-Claire, additional, Kim, Jiyoon L., additional, Pierce, Jason S., additional, Ogretmen, Besim, additional, Futerman, Anthony H., additional, and Thévenod, Frank, additional

Published
2022
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11. Teaching an old dog new tricks: reactivated developmental signaling pathways regulate ABCB1 and chemoresistance in cancer

Author

Wing-Kee Lee and Thévenod Frank

Subjects
biology, business.industry, biology.protein, Cancer research, medicine, Cancer, ATP-binding cassette transporter, Transforming growth factor beta, Drug resistance, Signal transduction, medicine.disease, business, Tumor heterogeneity
Abstract

Oncogenic multidrug resistance (MDR) is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters. Drug efflux transporters, particularly the MDR P-glycoprotein ABCB1, represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets, but also for inhibiting apoptotic cell death cues, such as removal of proapoptotic signals. Several cell populations exhibiting the MDR phenotype co-exist within a tumor, such as cells forming the bulk tumor cell mass, cancer stem cells, and cancer persister cells. The key to regulation of ABCB1 expression is the cellular transcriptional machinery. Developmental signaling pathways (e.g, Hedgehog, Notch, Wnt/β-catenin, TGFβ, PITX2) are pivotal in governing cell proliferation, survival, differentiation and guiding cell migration during embryogenesis, and their reactivation during carcinogenesis, which is of particular significance for tumor initiation, progression, and metastasis, also leads to the upregulation of ABCB1. These pathways also drive and maintain cancer cell stemness, for which ABCB1 is used as a marker. In this review, the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.

Published
2021

21. Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells

Author

Wolff Natascha A, Molitor Malte, Lee Wing-Kee, Chakraborty Prabir K, and Thévenod Frank

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The class 1 carcinogen cadmium (Cd2+) disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/β-catenin signaling are known to contribute to carcinogenesis. Results We investigated Wnt signaling after Cd2+-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC). Cd2+ (25 μM, 3-9 h) caused nuclear translocation of β-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd2+ reduced the interaction of β-catenin with AJ components (E-cadherin, α-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. Wnt signaling elicited by Cd2+ was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd2+ toxicity. Cd2+ also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability. Conclusions Cd2+ induces Wnt signaling in PTC. Hence, Cd2+ may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.

Published
2010
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25. Biochemical and Structural Characterization of the Interaction between the Siderocalin NGAL/LCN2 (Neutrophil Gelatinase-associated Lipocalin/Lipocalin 2) and the N-terminal Domain of Its Endocytic Receptor SLC22A17

Author

Cabedo Martinez, Ana-Isabel, primary, Weinhäupl, Katharina, additional, Lee, Wing-Kee, additional, Wolff, Natascha A., additional, Storch, Barbara, additional, Żerko, Szymon, additional, Konrat, Robert, additional, Koźmiński, Wiktor, additional, Breuker, Kathrin, additional, Thévenod, Frank, additional, and Coudevylle, Nicolas, additional

Published
2016
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30. Effect of mycophenolic acid on TNFα-induced expression of cell adhesion molecules in human venous endothelial cells in vitro

Author

Hauser, Ingeborg A, Johnson, David R, Thévenod, Frank, and Goppelt-Strübe, Margarete

Subjects
Antibiotics, Antineoplastic, Guanosine, Tumor Necrosis Factor-alpha, NF-kappa B, Vascular Cell Adhesion Molecule-1, In Vitro Techniques, Mycophenolic Acid, Up-Regulation, Papers, Humans, Endothelium, Vascular, RNA, Messenger, E-Selectin, Cell Adhesion Molecules, Immunosuppressive Agents, Transcription Factors
Abstract

1. Mycophenolic acid (MPA) is an inhibitor of inosine-5'-monophosphate dehydrogenase and therefore interferes with cellular GTP biosynthesis. Recently, MPA has been used as an antiproliferative and immunosuppressive agent. In the present study, the effect of MPA on the expression of the endothelial cell adhesion molecules (CAMs), intercellular (I) CAM-1, vascular (V) CAM-1 and endothelial (E)-selectin, was investigated in tumour necrosis factor-alpha (TNF alpha)-activated cultured human venous endothelial cells (EC). 2. Surface expression of CAMs was measured by flow cytometry and mRNA expression by Northern blot analysis. Transcriptional activation of CAMs by the nuclear factor NF-kappaB was determined by an electromobility shift assay. The function of CAMs was studied by a static adhesion assay with human monocyte-like undifferentiated U937 cells. 3. Pretreatment of TNF alpha- (5 ng ml(-1), 12 h) activated EC with MPA (10 microM, 24 h) increased the binding of U937 cells, which had not been treated with MPA, by approximately 2 fold. MPA-pretreatment of EC did not affect TNF alpha-induced surface expression of ICAM-1. However, VCAM-1 and E-selectin were increased 2-3 fold and remained elevated up to 24 h, by which time TNF alpha-activated control EC had returned to baseline levels of expression. The effect of MPA on the surface expression of CAMs was half-maximal at approximately 1 microM and requiredor = 12 h of pretreatment. Guanosine (0.3 mM), a precursor of GTP, did not prevent the effect of MPA on the expression of CAMs in TNF alpha-activated EC. 4. Kinetics of mRNA expression of CAMs mirrored protein expression: mRNA for ICAM-1 was unaffected, whereas TNF alpha-induced mRNA expression for E-selectin and VCAM-1 was prolonged and increased by MPA. This effect was not due to increased transcription mediated by the nuclear transcription factor NF-kappaB. However, half-life for E-selectin mRNA was increased 10 fold by MPA, whereas ICAM-1 mRNA half-life was unchanged. 5. The data demonstrate that apart from its antiproliferative effects on lymphocytes, MPA enhances TNF alpha-induced VCAM-1 and E-selectin surface expression on EC by selectively increasing the mRNA-stability of these cell adhesion molecules. This effect of MPA on EC appears to be independent from inhibition of inosine-5'-monophosphate dehydrogenase.

Published
1997

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