Relevant bibliographies by topics / Monocarboxylate transporters (MCT)

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  2. Dissertations / Theses
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Academic literature on the topic 'Monocarboxylate transporters (MCT)'

Author: Grafiati
Published: 4 June 2021
Last updated: 1 February 2022

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Journal articles on the topic "Monocarboxylate transporters (MCT)"

1

DIMMER, Kai-Stefan, Björn FRIEDRICH, Florian LANG, Joachim W. DEITMER, and Stefan BRÖER. "The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells." Biochemical Journal 350, no. 1 (August 9, 2000): 219–27. http://dx.doi.org/10.1042/bj3500219.

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Transport of lactate and other monocarboxylates in mammalian cells is mediated by a family of transporters, designated monocarboxylate transporters (MCTs). The MCT4 member of this family has recently been identified as the major isoform of white muscle cells, mediating lactate efflux out of glycolytically active myocytes [Wilson, Jackson, Heddle, Price, Pilegaard, Juel, Bonen, Montgomery, Hutter and Halestrap (1998) J. Biol. Chem. 273, 15920–15926]. To analyse the functional properties of this transporter, rat MCT4 was expressed in Xenopus laevis oocytes and transport activity was monitored by flux measurements with radioactive tracers and by changes of the cytosolic pH using pH-sensitive microelectrodes. Similar to other members of this family, monocarboxylate transport via MCT4 is accompanied by the transport of H+ across the plasma membrane. Uptake of lactate strongly increased with decreasing extracellular pH, which resulted from a concomitant drop in the Km value. MCT4 could be distinguished from the other isoforms mainly in two respects. First, MCT4 is a low-affinity MCT: for l-lactate Km values of 17±3mM (pH-electrode) and 34±5mM (flux measurements with l-[U-14C]lactate) were determined. Secondly, lactate is the preferred substrate of MCT4. Km values of other monocarboxylates were either similar to the Km value for lactate (pyruvate, 2-oxoisohexanoate, 2-oxoisopentanoate, acetoacetate) or displayed much lower affinity for the transporter (β-hydroxybutyrate and short-chain fatty acids). Under physiological conditions, rat MCT will therefore preferentially transport lactate. Monocarboxylate transport via MCT4 could be competitively inhibited by α-cyano-4-hydroxycinnamate, phloretin and partly by 4,4´-di-isothiocyanostilbene-2,2´-disulphonic acid. Similar to MCT1, monocarboxylate transport via MCT4 was sensitive to inhibition by the thiol reagent p-chloromercuribenzoesulphonic acid.
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Becker, Helen M., Nilufar Mohebbi, Angelica Perna, Vadivel Ganapathy, Giovambattista Capasso, and Carsten A. Wagner. "Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis." American Journal of Physiology-Renal Physiology 299, no. 1 (July 2010): F141—F154. http://dx.doi.org/10.1152/ajprenal.00488.2009.

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The monocarboxylate transporter family (MCT) comprises 14 members with distinct transport properties and tissue distribution. The kidney expresses several members of the MCT family, but only little is known about their exact distribution and function. Here, we investigated selected members of the MCT family in the mouse kidney. MCT1, MCT2, MCT7, and MCT8 localized to basolateral membranes of the epithelial cells lining the nephron. MCT1 and MCT8 were detected in proximal tubule cells whereas MCT7 and MCT2 were located in the thick ascending limb and the distal tubule. CD147, a β-subunit of MCT1 and MCT4, showed partially overlapping expression with MCT1 and MCT2. However, CD147 was also found in intercalated cells. We also detected SMCT1 and SMCT2, two Na+-dependent monocarboxylate cotransporters, on the luminal membrane of type A intercalated cells. Moreover, mice were given an acid load for 2 and 7 days. Acidotic animals showed a marked but transient increase in urinary lactate excretion. During acidosis, a downregulation of MCT1, MCT8, and SMCT2 was observed at the mRNA level, whereas MCT7 and SMCT1 showed increased mRNA abundance. Only MCT7 showed lower protein abundance whereas all other transporters remained unchanged. In summary, we describe for the first time the localization of various MCT transporters in mammalian kidney and demonstrate that metabolic acidosis induces a transient increase in urinary lactate excretion paralleled by lower MCT7 protein expression.
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Wang, X., A. J. Levi, and A. P. Halestrap. "Substrate and inhibitor specificities of the monocarboxylate transporters of single rat heart cells." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 2 (February 1, 1996): H476—H484. http://dx.doi.org/10.1152/ajpheart.1996.270.2.h476.

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We have used the intracellular pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF) to characterize the substrate and inhibitor specificity of monocarboxylate transport into isolated rat heart cells. Further evidence was obtained for the presence of two lactate carriers present in heart cells (Wang et al., Biochem. J. 290: 249-258, 1993) both distinct from the recently cloned monocarboxylate transporter isoform 1 (MCT-1) found in many other cell types. Only one isoform was potently inhibited by alpha-cyano-4-hydroxycinnamate [CHC; inhibitor constant (Ki) 190 microM] and the stilbene disulfonates 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (Ki 79 microM) and 4,4'-dinitrostilbene-2,2'-disulfonate (Ki of cis- and trans-isomers 38 and 171 microM, respectively; neither isomer inhibits MCT-1). The second carrier had a Ki of approximately 3 mM for CHC and 0.5-2 mM for the stilbene disulfonates. Thus, unlike in many other tissues, in rat heart cells these inhibitors are not effective at blocking lactate transport totally unless used at very high concentrations. Both carriers were inhibited by 3-isobutyl-1-methylxanthine (Ki 340 microM) and neither by 5-nitro-2-(3-phenylpropylamino)benzoate (a potent inhibitor of MCT-1). The overall Michaelis constant (Km) and maximum reaction rate (Vmax) for transport of a variety of substituted monocarboxylates (C2-C5) were determined, although it was not possible to elucidate the kinetic parameters of the two isoforms. Of physiological interest, the ketone bodies D-beta-hydroxybutyrate and acetoacetate had K(m) values of 10 and 5.4 mM, respectively. Vmax values were similar to those of L-lactate and pyruvate and indicate that transport could limit rates of utilization of ketone bodies. No stereoselectivity for L-over D-isomers of 2-chloro or 2-hydroxy acids was observed.
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Chidlow, Glyn, John P. M. Wood, Mark Graham, and Neville N. Osborne. "Expression of monocarboxylate transporters in rat ocular tissues." American Journal of Physiology-Cell Physiology 288, no. 2 (February 2005): C416—C428. http://dx.doi.org/10.1152/ajpcell.00037.2004.

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The aim of the present study was to determine the distribution of monocarboxylate transporter (MCT) subtypes 1-4 in the various structures of the rat eye by using a combination of conventional and real-time RT-PCR, immunoblotting, and immunohistochemistry. Retinal samples expressed mRNAs encoding all four MCTs. MCT1 immunoreactivity was observed in photoreceptor inner segments, Müller cells, retinal capillaries, and the two plexiform layers. MCT2 labeling was concentrated in the inner and outer plexiform layers. MCT4 immunolabeling was present only in the inner retina, particularly in putative Müller cells, and the plexiform layers. No MCT3 labeling could be observed. The retinal pigment epithelium (RPE)/choroid expressed high levels of MCT1 and MCT3 mRNAs but lower levels of MCT2 and MCT4 mRNAs. MCT1 was localized to the apical and MCT3 to the basal membrane of the RPE, whereas MCT2 staining was faint. Although MCT1-MCT4 mRNAs were all detectable in iris and ciliary body samples, only MCT1 and MCT2 proteins were expressed. These were present in the iris epithelium and the nonpigmented epithelium of the ciliary processes. MCT4 was localized to the smooth muscle lining of large vessels in the iris-ciliary body and choroid. In the cornea, MCT1 and MCT2 mRNAs and proteins were detectable in the epithelium and endothelium, whereas evidence was found for the presence of MCT4 and, to a lesser extent, MCT1 in the lens epithelium. The unique distribution of MCT subtypes in the eye is indicative of the pivotal role that these transporters play in the maintenance of ocular function.
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Visser, W. Edward, Edith C. H. Friesema, and Theo J. Visser. "Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns." Molecular Endocrinology 25, no. 1 (January 1, 2011): 1–14. http://dx.doi.org/10.1210/me.2010-0095.

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The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.
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Groeneweg, Stefan, Ferdy S. van Geest, Robin P. Peeters, Heike Heuer, and W. Edward Visser. "Thyroid Hormone Transporters." Endocrine Reviews 41, no. 2 (November 22, 2019): 146–201. http://dx.doi.org/10.1210/endrev/bnz008.

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Abstract Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease.
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PRICE, T. Nigel, N. Vicky JACKSON, and P. Andrew HALESTRAP. "Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past." Biochemical Journal 329, no. 2 (January 15, 1998): 321–28. http://dx.doi.org/10.1042/bj3290321.

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Measurement of monocarboxylate transport kinetics in a range of cell types has provided strong circumstantial evidence for a family of monocarboxylate transporters (MCTs). Two mammalian MCT isoforms (MCT1 and MCT2) and a chicken isoform (REMP or MCT3) have already been cloned, sequenced and expressed, and another MCT-like sequence (XPCT) has been identified. Here we report the identification of new human MCT homologues in the database of expression sequence tags and the cloning and sequencing of four new full-length MCT-like sequences from human cDNA libraries, which we have denoted MCT3, MCT4, MCT5 and MCT6. Northern blotting revealed a unique tissue distribution for the expression of mRNA for each of the seven putative MCT isoforms (MCT1-MCT6 and XPCT). All sequences were predicted to have 12 transmembrane (TM) helical domains with a large intracellular loop between TM6 and TM7. Multiple sequence alignments showed identities ranging from 20% to 55%, with the greatest conservation in the predicted TM regions and more variation in the C-terminal than the N-terminal region. Searching of additional sequence databases identified candidate MCT homologues from the yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the archaebacterium Sulfolobus solfataricus. Together these sequences constitute a new family of transporters with some strongly conserved sequence motifs, the possible functions of which are discussed.
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Omlin, Teye, and Jean-Michel Weber. "Exhausting exercise and tissue-specific expression of monocarboxylate transporters in rainbow trout." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 304, no. 11 (June 1, 2013): R1036—R1043. http://dx.doi.org/10.1152/ajpregu.00516.2012.

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Transmembrane lactate movements are mediated by monocarboxylate transporters (MCTs), but these proteins have never been characterized in rainbow trout. Our goals were to clone potential trout MCTs, determine tissue distribution, and quantify the effects of exhausting exercise on MCT expression. Such information could prove important to understand the mechanisms underlying the classic “lactate retention ” seen in trout white muscle after intense exercise. Four isoforms were identified and partially characterized in rainbow trout: MCT1a, MCT1b, MCT2, and MCT4. MCT1b was the most abundant in heart and red muscle but poorly expressed in the gill and brain where MCT1a and MCT2 were prevalent. MCT expression was strongly stimulated by exhausting exercise in brain (MCT2: +260%) and heart (MCT1a: +90% and MCT1b: +50%), possibly to increase capacity for lactate uptake in these highly oxidative tissues. By contrast, the MCTs of gill, liver, and muscle remained unaffected by exercise. This study provides a possible functional explanation for postexercise “lactate retention” in trout white muscle. Rainbow trout may be unable to release large lactate loads rapidly during recovery because: 1) they only poorly express MCT4, the main lactate exporter found in mammalian glycolytic muscles; 2) the combined expression of all trout MCTs is much lower in white muscle than in any other tissue; and 3) exhausting exercise fails to upregulate white muscle MCT expression. In this tissue, carbohydrates act as an “energy spring” that alternates between explosive power release during intense swimming (glycogen to lactate) and recoil during protracted recovery (slow glycogen resynthesis from local lactate).
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Bader, Annika, and Eric Beitz. "Transmembrane Facilitation of Lactate/H+ Instead of Lactic Acid Is Not a Question of Semantics but of Cell Viability." Membranes 10, no. 9 (September 15, 2020): 236. http://dx.doi.org/10.3390/membranes10090236.

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Transmembrane transport of monocarboxylates is conferred by structurally diverse membrane proteins. Here, we describe the pH dependence of lactic acid/lactate facilitation of an aquaporin (AQP9), a monocarboxylate transporter (MCT1, SLC16A1), and a formate–nitrite transporter (plasmodium falciparum FNT, PfFNT) in the equilibrium transport state. FNTs exhibit a channel-like structure mimicking the aquaporin-fold, yet act as secondary active transporters. We used radiolabeled lactate to monitor uptake via yeast-expressed AQP9, MCT1, and PfFNT for long enough time periods to reach the equilibrium state in which import and export rates are balanced. We confirmed that AQP9 behaved perfectly equilibrative for lactic acid, i.e., the neutral lactic acid molecule enters and passes the channel. MCT1, in turn, actively used the transmembrane proton gradient and acted as a lactate/H+ co-transporter. PfFNT behaved highly similar to the MCT in terms of transport properties, although it does not adhere to the classical alternating access transporter model. Instead, the FNT appears to use the proton gradient to neutralize the lactate anion in the protein’s vestibule to generate lactic acid in a place that traverses the central hydrophobic transport path. In conclusion, we propose to include FNT-type proteins into a more generalized, function-based transporter definition.
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Jansen, S., M. Pantaleon, and P. Kaye. "236.Differential expression of monocarboxylate cotransporter proteins in preimplantation embryos." Reproduction, Fertility and Development 16, no. 9 (2004): 236. http://dx.doi.org/10.1071/srb04abs236.

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During preimplantation development mouse embryos demonstrate a switch in substrate preference. Pyruvate consumption, high during the first few cleavage stages, declines as the morula develops to a blastocyst, when glucose becomes the preferred substrate. Whilst pyruvate utilisation has been well characterised, changes in the function and expression of pyruvate transporters during this crucial period remain unclear. Pyruvate, lactate and other monocarboxylates are transported across mammalian cell membranes via a specific H+-monocarboxylate cotransporter (MCT). Fourteen members of this family have been identified of which MCT1, MCT2 and MCT4 are well characterised. Although mRNA expression profiles are known during early mouse development (1,2), the specific roles of each protein isoform are unknown. In order to understand these, the expression pattern for each isoform and their cellular localisation during preimplantation development have been determined. Mouse embryos were freshly collected from superovulated Quackenbush mice at 24, 48, 72 and 96 h post-hCG and expression of MCT1, MCT2 and MCT4 analysed by confocal laser scanning immunohistochemistry. Our results confirm that all three MCT proteins are expressed in preimplantation embryos. Immunoreactivity for MCT1 and MCT2 appears diffuse throughout the cytoplasm of cleavage stage embryos. As development proceeds, MCT1 localised to the basolateral membranes of morulae and blastocysts, whilst stronger MCT2 expression was found on the apical trophectoderm as well as the inner cell mass. MCT4 immunoreactivity on the other hand is apparent at cell-cell contact sites in cleavage stage embryos and morulae, but it is not apparent in the blastocyst. The demonstration of different expression patterns for MCT1, MCT2 and MCT4 in mouse embryos implies specific functional roles for each in the critical regulation of H+, pyruvate and lactate transport during preimplantation development. (1) Harding EA, Day ML, Gibb CA, Johnson MH, Cook DI (1999) The activity of the H+-monocarboxylate cotransporter during pre-implantation development in the mouse. Eur. J. Physiol. 438, 397–404. (2) H�rubel F, El Mouatassim S, Gu�rin P, Frydman R, M�n�zo Y (2002) Genetic expression of monocarboxylate transporters during human and murine oocyte maturation and early embryonic development. Zygote 10, 175–181.
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Dissertations / Theses on the topic "Monocarboxylate transporters (MCT)"

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Manning, Fox Jocelyn Elizabeth. "Expression and characterisation of novel mammalian monocarboxylate transporters." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324339.

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Clapham, Chloe. "Targeting cell metabolism in chronic lymphocytic leukaemia (CLL) through the inhibition of monocarboxylate transporters (MCT) -1 and -4." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2010021/.

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Chronic lymphocytic leukaemia (CLL) is a lymphoid malignancy which despite advances in the treatment options available is still incurable. Characterised by the gradual accumulation of CD5+ B cells, the paradigm that this is due to failed apoptosis has been challenged and a significant proliferative component has been identified. However, despite the crosstalk between pathways which regulate metabolism and proliferation the metabolic characteristics of these cells are not fully understood. Furthermore, there is a renewed interest in the field of cancer cell metabolism because of the Warburg effect, a hallmark of malignancy whereby cells preferentially switch to aerobic glycolysis and rapidly consume glucose. This has led to the development of new drugs such as AZD3965 an inhibitor of monocarboxylate transporter 1 (MCT1), which along with MCT4 mediates the export of lactate, a toxic bi-product of glycolysis, out of the cell. The aim of this project was to assess whether therapeutically targeting MCT -1 and -4 would be a viable approach for CLL. Chapter 2 of this thesis examines expression of MCT -1 and -4 as well as a specific chaperone protein needed for the surface expression of these proteins, CD147. This chapter confirms the presence of both MCT -1 and -4 and CD147 in normal B cells as well as demonstrating for the first time that these transporters are expressed in CLL cells using Western blotting and qRT-PCR to assess the MCTs and flow cytometry to measure CD147. The levels of both MCTs and CD147 are demonstrated to be significantly reduced in CLL cells in comparison normal B cells likely due to the adoption of a quiescent phenotype to aid cell survival. The following chapter investigates this further by assessing whether there are any changes in expression under the influence of microenvironmental stimuli, specifically CD40 ligand (CD40L). In this chapter it is demonstrated for the first time that MCT4 is upregulated in CLL cells in response to CD40L. Analysis of gene expression using a Fluidigm Biomark™ array suggests this is due to the induction of glycolysis and that CLL cells may promote fatty acid synthesis as well as instigating changes in the metabolism of the tumour stroma possibly to provide substrates. Finally, chapter 4 evaluates the sensitivity of CLL cell lines to AZD3965 using cell death and cell viability assays. Both MEC-1 and HG3 CLL cell lines are shown to be resistant to MCT1 inhibition using AZD3965 and silencing of MCT4 using siRNA cells also has no effect on the viability of MEC-1 cells. That MCT4 can compensate for MCT1 inhibition is shown by the transient expression of MCT4 in a Raji cell line where only MCT1 is expressed. Taken together, the data presented in this study indicates that while the inhibition of MCT1 is likely to be ineffective dual inhibition of both MCT -1 and -4 may be a viable strategy for the localised inhibition of CLL in the secondary tissues. Furthermore, MCT inhibition in this disease may have the potential to negate mechanisms of resistance and protection from oxidative stress mediated by CD40L.
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Fong, Joseph D. "The Distinction of the Interactions Between the Transmembrane Domains of Basigin Gene Products and Monocarboxylate Transporters." UNF Digital Commons, 2018. https://digitalcommons.unf.edu/etd/788.

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Although it was once thought that neurons solely rely on glucose as a substrate for cellular energy production, it is now known that small monocarboxylate molecules, like pyruvate, lactate, and ketone bodies, are also utilized. Monocarboxylates are transported across plasma membranes via facilitated diffusion using a family of transport proteins known as monocarboxylate transporters (MCTs). Four MCTs (MCT1, MCT2, MCT3, and MCT4) are expressed within neural tissues. Expression of the MCTs has been tied to co-expression of a cell adhesion molecule belonging to the Basigin subset of the immunoglobulin superfamily (IgSF). Basigin gene products are known to interact with MCT1 and MCT4 in the mammalian neural retina and this association is essential to support the cellular energy needs of photoreceptors. A previous study indicated that Basigin gene products use hydrophobic amino acids within specific regions of the transmembrane domain to interact with MCT1. In the present study, it is hypothesized that the same amino acids within the transmembrane domain are used to interact with MCT4, but that no association exists with MCT2, which typically interacts with a different member of the IgSF subset. Therefore, the purpose of the present study was to assess the association between Basigin gene products and MCT4, and with MCT2. Recombinant proteins corresponding to the transmembrane domain of Basigin gene products were used in in vitro binding assays with endogenous MCT2 and MCT4 from mouse brain protein lysates. Contrary to the hypothesis, it was determined that the transmembrane domain of Basigin gene products binds to both MCT2 and MCT4 in vitro. Different amino acids within the transmembrane domain of Basigin gene products are used for each association and the pattern is different from that used in the association with MCT1. The data suggest that Basigin plays multiple roles in the nervous system.
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Marchiq, Ibtissam. "Hypoxie et métabolisme tumoral : analyse génétique et fonctionnelle des symporteurs H+/lactate et de leur chaperone, BASIGINE." Thesis, Nice, 2015. http://www.theses.fr/2015NICE4066/document.

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Le catabolisme exacerbé du glucose et de la glutamine est actuellement reconnu comme une caractéristique des cellules cancéreuses, qui leur procure un avantage prolifératif via la production et l’accumulation de plusieurs métabolites au niveau du microenvironnement. Parmi ces métabolites, l’acide lactique représente une molécule de signalisation clé, favorisant la migration et les métastases. Mon projet de thèse s’inscrit dans le contexte d’une étude du métabolisme glycolytique associé aux cellules tumorales à division rapide. Durant ce projet, nous nous sommes intéressés à la caractérisation génétique et fonctionnelle des transporteurs MCT (MonoCarboxylate Transporters) 1 et 4, qui sont des symporteurs H+/lactate dont l’expression membranaire et la fonctionnalité requièrent la liaison avec une protéine chaperonne : CD147/BASIGINE (BSG). Afin de mieux explorer la physiologie des complexes MCT/BSG, et valider le ciblage de l’export d’acide lactique comme une nouvelle approche anti-cancer, nous avons développé une stratégie visant à invalider le gène BSG et/ou MCT4, en utilisant la technologie des Zinc Finger Nucleases (ZFN), dans des lignées cellulaires cancéreuses humaines de côlon, poumon et glioblastome. D’abord, nous avons démontré, que l’effet pro-tumoral majeur de BSG est lié à son action directe sur la stabilisation des MCTs au niveau des tumeurs glycolytiques et non pas à la production des metalloprotéases. Ensuite, nous avons démontré pour la première fois que l’inhibition concomitante de MCT1 et MCT4 est nécessaire pour induire une baisse significative de la tumorigénécité in vivo
Enhanced glucose and glutamine catabolism has become a recognized feature of cancer cells, leading to accumulation of metabolites in the tumour microenvironment, which offers growth advantages to tumours. Among these metabolites is emerging as a key signalling molecule that plays a pivotal role in cancer cell migration and metastasis. In this thesis, we focused on the genetic and functional characterization of monocarboxylate transporters (MCT) 1 and 4, which are H+/lactate symporters that require an interaction with an ancillary protein, CD147/BASIGIN (BSG), for their plasma membrane expression and function. To further explore the physiology of MCT/BSG complexes and validate the blockade of lactic acid export as an anti-cancer strategy, we designed experiments using Zinc Finger Nuclease mediated BSG and/or MCT4 gene knockouts in human colon adenocarcinoma, lung carcinoma and glioblastoma cell lines. First of all, we demonstrated that the major protumoural action of BSG is to control the energetics of glycolytic tumours via MCT1/4 activity and not to produce matrix metalloproteases. Second, we showed for the first time that combined inhibition of both MCT1 and MCT4 transporters is required to achieve a significant reduction in the tumour growth in vivo. Moreover, our findings reported that disruption of the BSG gene dramatically reduced the plasma membrane expression and lactate transport activity of both MCT1 and MCT4, leading to increased accumulation of intracellular pools of lactic and pyruvic acids, decreased intracellular pH and reduced rate of glycolysis
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Lagarde, Damien. "Rôle des flux de lactate dans le métabolisme des tissus adipeux beiges et bruns." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30146.

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Les tissus adipeux thermogéniques beiges et bruns améliorent l'homéostasie énergétique et représentent des cibles thérapeutiques potentielles pour traiter les maladies métaboliques associées à l’obésité et au vieillissement. Malgré des décennies de recherche et le rôle très bien décrit de la signalisation noradrénergique, les mécanismes sous-jacents à leur plasticité, leur activation et leur fonction restent encore mal compris. Contrairement au tissu adipeux blanc qui stocke l’énergie pour la mettre à disposition de l'organisme, le tissu adipeux brun la dissipe sous forme de chaleur, et participe à la thermogénèse de non frisson. Cette spécificité métabolique est permise par les adipocytes bruns, aux fortes capacités oxydatives dues à leur richesse en mitochondries et à l’expression de la protéine découplante UCP1 (Uncoupling Protein 1). Les adipocytes beiges présentent des caractéristiques métaboliques similaires mais apparaissent dans des zones spécifiques de certains tissus adipeux blancs par le phénomène de brunissement, suite à une stimulation comme l’exposition au froid. Cependant, ces cellules apparaissent dans d’autres conditions de stress, ce qui suggère qu’elles puissent assurer d’autres fonctions que la thermogenèse. Les travaux de mon équipe ont montré que le lactate et les corps cétoniques, des métabolites produits lorsque les flux de substrats (glucose et acides gras respectivement) dépassent les capacités oxydatives et qui agissent comme des régulateurs du métabolisme redox au travers de dialogues inter-cellulaires et inter-tissulaires, sont de puissants inducteurs du brunissement. L’induction d’UCP1 par ces métabolites passe par un mécanisme dépendant du potentiel red/ox (augmentation du ratio NADH,H+/NAD+), et comme UCP1 permet de diminuer ce potentiel red/ox en accélérant le fonctionnement de la chaîne respiratoire, le brunissement apparaît comme un mécanisme adaptatif pour maintenir l’homéostasie red/ox
Brown and beige thermogenic adipose tissues improve energetic homeostasis and represent a potential therapeutic targets for the treatment of obesity and aging associated metabolic diseases. Besides decades of research and the very well-described role of noradrenergic signaling, the mechanisms underlying their plasticity, activation and function are still poorly understood. In contrast to white adipose tissue that stores energy to make it available to the organism, brown adipose tissue dissipates energy as heat, and is involved in non-shivering thermogenesis. This metabolic specificity is permitted by brown adipocytes, which exhibit strong oxidative capacities due to their high content in mitochondria and the expression of the uncoupling protein 1 (UCP1). Beige adipocytes have similar metabolic characteristics but appear in specific regions of certain white adipose tissues by the browning phenomenon, following stimulation such as cold exposure. However, these cells appear in other stress situations, suggesting that they may have other functions than thermogenesis. My team's work has previously shown that lactate and ketone bodies, metabolites produced when substrate fluxes (glucose and fatty acids respectively) exceed oxidative capacities and act as regulators of redox metabolism through inter-cellular and inter-organ dialogues, are powerful inducers of browning. The induction of UCP1 by these metabolites is due to a redox mechanism (increase in NADH,H+/NAD+ ratio), and because UCP1 reduces this redox pressure by accelerating the respiratory chain, browning thus appears as an adaptive mechanism to maintain redox homeostasis. Because the underlying molecular mechanisms were poorly understood, my thesis objective was to characterize the expression of lactate transporters in adipocytes and to understand their role in their plasticity and metabolic activity. The fine mapping of the subcutaneous inguinal adipose tissue in mice, using laser microdissection experiments, gene expression measurement and confocal imaging, revealed i) a strong positive correlation between the expression of the lactate transporter Mct1 (monocarboxylate transporter 1) and that of Ucp1 and (ii) the appearance of UCP1 following cold exposure restricted to the subpopulation of adipocytes expressing MCT1 and pre-existing at thermoneutrality. These results highlight the MCT1 protein as a marker of dormant beige adipocytes, able of be activated during cold exposure. This finding is reinforced by the absence of the MCT1 protein in perigonadic adipose tissue which is resistant to browning, and its strong expression in classical brown adipocytes. While MCT1 is necessary for lactate-induced UCP1 expression, we showed that it was not involved in the Ucp1 regulation by adrenergic signaling. However, lactate oxidation and isotopic profiling experiments showed that MCT1 was essential for the metabolic activity of beige adipocytes, by controlling lactate export and import. Lactate export by MCT1 is necessary for glucose consumption, especially during ß3 adrenergic agonist stimulation, by maintaining the redox NADH,H+/NAD+ ratio which is fundamental for the control of glycolysis. MCT1-dependent lactate import feeds the oxidative metabolism and kreb cycle of these cells. A genetically engineered mouse model showed that inducible MCT1 loss of function in adipocytes impact glycemia during cold exposure, confirming the crucial role of MCT1 and lactate fluxes in the control of glucose metabolism in brown/beige adipose tissues. The proposed mechanisms highlight the fundamental role of MCT1 in beige adipocytes biology and could be extrapolated to brown adipocytes
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Omlin, Teye D. "Effects of Hypoxia and Exercise on In Vivo Lactate Kinetics and Expression of Monocarboxylate Transporters in Rainbow Trout." Thèse, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30652.

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The current understanding of lactate metabolism in fish is based almost entirely on interpretation of concentration measurements that cannot be used to infer changes in flux. Moreover, the transporters regulating these fluxes have never been characterized in rainbow trout. My goals were: (1) to quantify lactate fluxes in rainbow trout under normoxic resting conditions, during acute hypoxia, and exercise by continuous infusion of [U-14C] lactate; (2) to determine lactate uptake capacity of trout tissues by infusing exogenous lactate in fish rest and during graded exercise, and (3) to clone monocarboxylate transporters (MCTs) and determine the effects of exhausting exercise on their expression. Such information could prove important to understand the mechanisms underlying the classic “lactate retention” seen in trout white muscle after intense exercise. In normoxic resting fish, the rates of appearance (Ra) and disappearance (Rd) of lactate were always matched (~18 to 13 µmol kg-1 min-1), thereby maintaining a low baseline blood lactate concentration (~0.8 mM). In hypoxic fish, Ra lactate increased from baseline to 36.5 µmol kg-1 min-1, and was accompanied by an unexpected 52% increase in Rd reaching 30.3 µmol kg-1 min-1, accounting for a rise in blood lactate to 8.9 mM. In exercising fish, lactate flux was stimulated > 2.4 body lengths per second (BL s-1). As the fish reached critical swimming speed (Ucrit), Ra lactate was more stimulated (+67% to 40.4 μmol kg-1 min-1) than Rd (+41% to 34.7 μmol kg-1 min-1), causing an increase in blood lactate to 5.1mM. Fish infused with exogenous lactate stimulated Rd lactate by 300% (14 to 56 μmol kg-1 min-1) during graded exercise, whereas the Rd in resting fish increased by only 90% (21 to 40 µmol kg-1 min-1). Four MCT isoforms were partially cloned and characterized in rainbow trout: MCT1b was the most abundant in heart, and red muscle, but poorly expressed in gill and brain where MCT1a and MCT2 were prevalent. MCT4 was more expressed in the heart. Transcript levels of MCT2 (+260%; brain), MCT1a (+90%; heart) and MCT1b (+50%; heart) were stimulated by exhausting exercise. This study shows that: (i) the increase in Rd lactate plays a strategic role in reducing the lactate load imposed on the circulation. Without this response, blood lactate accumulation would double; (ii) a high capacity for lactate disposal in rainbow trout tissues is elicited by the increased blood-to-tissue lactate gradient when extra lactate is administered; and (iii) rainbow trout may be unable to release large lactate loads rapidly from white muscle after exhausting exercise (lactate retention) because they poorly express MCT4 in white muscle and fail to upregulate its expression during exercise.
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Richards, William. "The influence of aging and cardiovascular training status upon monocarboxylate transporters." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1133362045.

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Hutchinson, Laura. "The role and therapeutic significance of monocarboxylate transporters in prostate cancer." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/the-role-and-therapeutic-significance-of-monocarboxylate-transporters-in-prostate-cancer(280f6221-d12b-4ca9-9322-e0ba1f5511f6).html.

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It has been shown that tumour cells are capable of switching to glycolytic metabolism for the production of ATP even in the presence of oxygen, this is known as aerobic glycolysis or the 'Warburg effect'. The glycolytic phenotype has been associated with tumour aggressiveness and poor outcome in several cancer types. This makes the area of cancer metabolism an attractive area for the potential identification of new therapeutic targets. One key component, required for cells to maintain the glycolytic phenotype, is the presence of monocarboxylate transporters that are capable of exporting lactate. These transporters are vital for the maintenance of the intracellular pH of cells under these conditions. This study was centred around the hypothesis that altering expression of MCTs would impact on the metabolism of tumour cells and, therefore, other key characteristics of cells relating to metastatic capabilities and survival following treatment. For the purpose of this work, prostate cancer cell lines were transfected with lentiviral particles targeting overexpression of MCT1 or MCT4, or knockdown of MCT4. Following transfection, cellular metabolic profiles were assessed under normoxic and hypoxic conditions and the metastatic phenotype of each cell line was investigated. Additionally, the effect of MCT expression on response to chemotherapy and radiation therapy was explored, and a siRNA metabolome screen was performed to identify combinations of targets that may produce synthetic lethality in prostate cancer cell lines. It was shown that changes in the expression of MCT1 or MCT4 did not cause significant changes in the metastatic phenotypes of the prostate cancer cell lines investigated. Some differences were observed in the metabolic pathways used by these prostate cancer cells following alterations in MCT expression. For example, overexpression of MCT1 in DU145 cells resulted in an increase in intracellular lactate. Additionally, MCT4 knockdown in PC3 cells was able to reduce OXPHOS under reduced oxygen. MCT1 overexpression was able to sensitise androgen-independent prostate cancer cells to treatment with chemotherapy and radiation therapy. Furthermore, combinations of siRNA treatments were identified that may be capable of producing synthetic lethality. In summary, findings in this study indicated that targeting MCT1 and MCT4 expression could offer therapeutic benefit in prostate cancer. However, it was also highlighted that the roles of these transporters are specific to cancer type, and even cell line.
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Little, L. Nicole. "Characterization of Basigin and the Interaction Between Embigin and Monocarboxylate Transporter -1, -2, and -4 (MCT1, MCT2, MCT4) in the Mouse Brain." UNF Digital Commons, 2011. http://digitalcommons.unf.edu/etd/384.

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Basigin and Embigin are members of the immunoglobulin superfamily that function as cell adhesion molecules. Studies of Basigin null mice revealed reproductive sterility, increased pain sensitivity, and blindness. It is thought that the mechanism causing blindness involves misexpression of monocarboxylate transporter 1 (MCT1) in the absence of Basigin. It is known that the transmembrane domain of Basigin interacts with MCT1. In the absence of Basigin, MCT1 does not localize to the plasma membrane of expressing cells and photoreceptor function is disrupted. Studies of the Basigin null mouse brain suggest that MCT1 is properly expressed, which suggests a separate mechanism causes the increased pain sensitivity in these animals, and also that a different protein directs MCT1 to the plasma membrane of expressing cells in mouse brain. Embigin is known to interact with MCT2 in neurons and with MCT1 in erythrocytes. It is not known, however, if Embigin normally interacts with MCT1 in the mouse brain or if Embigin acts to compensate for the lack of Basigin in the Basigin null animals. Therefore, the purpose of this study was to determine if Embigin normally interacts with MCT1, 2, or 4 in the mouse brain and if so, whether the interaction is similar to that between Basigin and MCT1. Expression of Basigin, Embigin, MCT1, MCT2, and MCT4 in mouse brain was assessed via immunoblotting and immunohistochemical analyses. In addition, recombinant protein probes corresponding to the Embigin transmembrane domain were generated for ELISA binding assays using endogenous mouse brain MCTs. It was determined that the proteins in question are rather ubiquitously expressed throughout the mouse brain, and that the cell adhesion molecules Basigin and Embigin may be co-expressed in the same cells as the MCT2 and MCT4 transporter proteins. In addition, it was determined that the Embigin transmembrane domain does not interact with the MCTs. The data therefore suggest that MCTs do not require Basigin or Embigin for plasma membrane expression in mouse brain.
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Cuff, Mark Anthony. "Role and regulation of the human colonic monocarboxylate transporter, MCT1." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250486.

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Book chapters on the topic "Monocarboxylate transporters (MCT)"

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Balasubramaniam, Shanti, Barry Lewis, Lawrence Greed, David Meili, Annegret Flier, Raina Yamamoto, Karmen Bilić, Claudia Till, and Jörn Oliver Sass. "Heterozygous Monocarboxylate Transporter 1 (MCT1, SLC16A1) Deficiency as a Cause of Recurrent Ketoacidosis." In JIMD Reports, 33–38. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/8904_2015_519.

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Mody, K., T. Kogai, and G. Brent. "Retinoic Acid Regulation of the Thyroid Hormone Transporter, Monocarboxylate Transporter 8 (Mct8), in Neural Differentiation." In The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego, P2–581—P2–581. Endocrine Society, 2010. http://dx.doi.org/10.1210/endo-meetings.2010.part2.p12.p2-581.

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Conference papers on the topic "Monocarboxylate transporters (MCT)"

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Palmer, M. "Monocarboxylate Transporter (MCT) Proteins as Targets for Radiation-Induced Pulmonary Fibrosis." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5338.

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Lim, Kah Suan, Kah Jing Lim, Brent A. Orr, Antoinette C. Price, Charles G. Eberhart, and Eli E. Bar. "Abstract 3483: Inhibition of Monocarboxylate Transporter 4 (MCT4) targets stem-like cells in glioblastoma." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-3483.

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Khalyfa, A., Z. Qiao, M. Raju, C. R. Shyu, A. Castro Grattoni, A. Ericsson, and D. Gozal. "Monocarboxylate Transporter-2 (MCT2) in Murine Model of Lung Cancer: A Multi-Omic Analysis." In American Thoracic Society 2021 International Conference, May 14-19, 2021 - San Diego, CA. American Thoracic Society, 2021. http://dx.doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4695.

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Beloueche-Babari, Mounia, Slawomir Wantuch, Markella Koniordou, Harry G. Parkes, Vaitha Arunan, Thomas R. Eykyn, Paul D. Smith, and Martin O. Leach. "Abstract C113: The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 triggers MCT4-dependent lactate accumulation and blocks pyruvate-lactate exchange in human cancer cells." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-c113.

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Khaleel, Anas, Abdallah A. Elbakkoush, Amneh Tarkhan, and Aiman Mahdi. "Microrna-1/206 Target both Monocarboxylate Transporter(MCT)-4 and Vascular Endothelial Growth Factor(VEGF)Genes Leading to Inhibition of Tumor Growth." In ICBRA '18: 2018 5th International Conference on Bioinformatics Research and Applications. New York, NY, USA: ACM, 2018. http://dx.doi.org/10.1145/3309129.3309144.

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Kunert, N., N. Ammar, F. Deisinger, N. Hedemann, C. Röcken, D. Bauerschlag, and H. Schäfer. "Rolle des reversen Warburg Metabolismus und der Monocarboxylat-Transporter-1 (MCT1)-vermittelten Laktataufnahme in der Chemoresistenz des Ovarialkarzinoms." In Kongressabstracts zur Gemeinsamen Jahrestagung der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) und der Bayerischen Gesellschaft für Geburtshilfe und Frauenheilkunde e.V. (BGGF). Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1730507.

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Critchlow, Susan E., Lorna Hopcroft, Lorraine Mooney, Nicola Curtis, Nicky Whalley, Haihong Zhong, Armelle Logie, et al. "Abstract 3224: Pre-clinical targeting of the metabolic phenotype of lymphoma by AZD3965, a selective inhibitor of monocarboxylate transporter 1 (MCT1)." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-3224.

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Polanski, Radoslaw, Cassandra L. Hodgkinson, Daisuke Nonaka, Lynsey Priest, Paul D. Smith, Fiona Blackhall, Christopher J. Morrow, and Caroline Dive. "Abstract 5434: Inhibition of monocarboxylate transporter 1 as a therapeutic strategy in small cell lung cancer: target validation studies using the MCT1 inhibitor AZD3965." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-5434.

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