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LKB1 induces apical trafficking of Silnoon, a monocarboxylate transporter, in Drosophila melanogaster.

ABSTRACT: Silnoon (Sln) is a monocarboxylate transporter (MCT) that mediates active transport of metabolic monocarboxylates such as butyrate and lactate. Here, we identify Sln as a novel LKB1-interacting protein using Drosophila melanogaster genetic modifier screening. Sln expression does not affect cell cycle progression or cell size but specifically enhances LKB1-dependent apoptosis and tissue size reduction. Conversely, down-regulation of Sln suppresses LKB1-dependent apoptosis, implicating Sln as a downstream mediator of LKB1. The kinase activity of LKB1 induces apical trafficking of Sln in polarized cells, and LKB1-dependent Sln trafficking is crucial for triggering apoptosis induced by extracellular butyrate. Given that LKB1 functions to control both epithelial polarity and cell death, we propose Sln is an important downstream target of LKB1.

SUBMITTER: Jang C

PROVIDER: S-EPMC2557035 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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LKB1 induces apical trafficking of Silnoon, a monocarboxylate transporter, in Drosophila melanogaster.

Jang Cholsoon C Lee Gina G Chung Jongkyeong J

The Journal of cell biology 20081001 1

Silnoon (Sln) is a monocarboxylate transporter (MCT) that mediates active transport of metabolic monocarboxylates such as butyrate and lactate. Here, we identify Sln as a novel LKB1-interacting protein using Drosophila melanogaster genetic modifier screening. Sln expression does not affect cell cycle progression or cell size but specifically enhances LKB1-dependent apoptosis and tissue size reduction. Conversely, down-regulation of Sln suppresses LKB1-dependent apoptosis, implicating Sln as a do ...[more]

PMID: 18838551

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Project description:IntroductionA sufficient dietary intake of the vitamin niacin is essential for normal cellular function. Niacin is transported into the cells by the monocarboxylate transporters: sodium-dependent monocarboxylate transporter (SMCT1 and SMCT2) and monocarboxylate transporter (MCT1). Despite the importance of niacin in biological systems, surprisingly, its in vivo biodistribution and trafficking in living organisms has not been reported. The availability of niacin radiolabelled with the short-lived positron emitting radionuclide carbon-11 ([11C]niacin) would enable the quantitative in vivo study of this endogenous micronutrient trafficking using in vivo PET molecular imaging.Methods[11C]Niacin was synthesised via a simple one-step, one-pot reaction in a fully automated system using cyclotron-produced carbon dioxide ([11C]CO2) and 3-pyridineboronic acid ester via a copper-mediated reaction. [11C]Niacin was administered intravenously in healthy anaesthetised mice placed in a high-resolution nanoScan PET/CT scanner. To further characterize in vivo [11C]niacin distribution in vivo, mice were challenged with either niacin or AZD3965, a potent and selective MCT1 inhibitor. To examine niacin gastrointestinal absorption and body distribution in vivo, no-carrier-added (NCA) and carrier-added (CA) [11C]niacin formulations were administered orally.ResultsTotal synthesis time including HPLC purification was 25 ± 1 min from end of [11C]CO2 delivery. [11C]Niacin was obtained with a decay corrected radiochemical yield of 17 ± 2%. We report a rapid radioactivity accumulation in the kidney, heart, eyes and liver of intravenously administered [11C]niacin which is consistent with the known in vivo SMCTs and MCT1 transporter tissue expression. Pre-administration of non-radioactive niacin decreased kidney-, heart-, ocular- and liver-uptake and increased urinary excretion of [11C]niacin. Pre-administration of AZD3965 selectively decreased [11C]niacin uptake in MCT1-expressing organs such as heart and retina. Following oral administration of NCA [11C]niacin, a high level of radioactivity accumulated in the intestines. CA abolished the intestinal accumulation of [11C]niacin resulting in a preferential distribution to all tissues expressing niacin transporters and the excretory organs.ConclusionsHere, we describe the efficient preparation of [11C]niacin as PET imaging agent for probing the trafficking of nutrient demand in healthy rodents by intravenous and oral administration, providing a translatable technique to enable the future exploration of niacin trafficking in humans and to assess its application as a research tool for metabolic disorders (dyslipidaemia) and cancer.

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LKB1 induces apical trafficking of Silnoon, a monocarboxylate transporter, in Drosophila melanogaster.

Publications

LKB1 induces apical trafficking of Silnoon, a monocarboxylate transporter, in Drosophila melanogaster.

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