The Human Monocarboxylate Transporter MCT1: Gene Structure and Regulation

Abstract

To the Editor:We read with concern the recent paper by Hadjiagapiou et al. (4) that examines the regulation of the monocarboxylate transporter isoform 1 (MCT1) gene promoter in Caco-2 cells and would like to make a number of comments with regard to 1) errors in their data and 2) misquotation and misrepresentation of prior publications by others in this important study area.MCT1 is the prototype of a family of proteins that play an important role in the transport of monocarboxylates across the cell membrane in a variety of cell types (5). MCT1 is particularly prominent in the colonic epithelium where it functions to transport short-chain fatty acids (most notably, butyrate) from the lumen across the colonocyte luminal membrane (7, 8). We demonstrated several years ago that MCT1 abundance is markedly downregulated during the transition from normality to malignancy in the colon and, more recently, that its expression is required for butyrate to exert many of its effects in cultured colonic epithelial cells (1, 6). Not surprisingly, the regulation of MCT1 expression in the intestine is an important area of study. We have previously reported that human colonic MCT1 expression is responsive to its substrate, butyrate, and that this regulation involves the dual control of transcription and mRNA stability (2). We have also determined the site of transcription initiation, isolated the MCT1 gene promoter, and demonstrated the MCT1 gene structure to comprise five exons interrupted by four introns. The first of these introns occurs in the 5'-untranslated region (UTR) encoding DNA, spans greater than 26 kb, and accounts for more than one-half of the entire MCT1 transcription unit (3).Given that the isolation of the human MCT1 gene promoter was first published in full more than three years ago (3) and the sequence submitted to the European Molecular Biology Laboratories database (Accession no. AJ438944), it is surprising that the first part of the paper by Hadjiagapiou et al. focuses on repetition of this isolation. This aside, a major concern is the inaccurate description by Hadjiagapiou et al. of where the MCT1 promoter DNA sequence is located in relation to the genome. The authors specifically and repeatedly state that the transcriptional start site is located only 281 bp upstream from the translational start site (i.e., the MCT1 coding region) and this is reinforced and illustrated by the contiguous DNA sequence shown in their Fig. 1. We want make it clear that these data are incorrect and ignore the large (26 kb) intron that interrupts the MCT1 5Ј-UTR (3). The presence of this intron is clearly indicated by a database blast of the MCT1 5Ј-RACE sequence, which shows that the sequence of the MCT1 message and that of the MCT1 genomic DNA diverge 45 bp upstream of the MCT1 coding region and only reconverge ϳ26 kb upstream in the genomic DNA. Moreover, this arrangement is described prominently in our prior publication detailing the first isolation of the MCT1 gene promoter and determination of the gene structure of human MCT...

Glucocorticoids differentially regulate Na-bile acid cotransport in normal and chronically inflamed rabbit ileal villus cells

“…Certain cis binding sites such as activator protein (AP)-1 or AP-2 motifs are located in the promotor region of some transport proteins that may bind to proinflammatory transcription factors during inflammation (4,9,23,24,54). By this mechanism the upregulated inflammatory mediators during inflammation may downregulate Na-solute cotransporters such as ASBT (26).…”