Molecular Identification and Functional Characterization of the Human Colonic Thiamine Pyrophosphate Transporter

Nabokina, Svetlana M.; Inoue, Katsuhisa; Subramanian, Veedamali S.; Valle, Judith E.; Yuasa, Hiroaki; Said, Hamid M.

doi:10.1074/jbc.m113.528257

Cited by 66 publications

(66 citation statements)

References 33 publications

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“…Thiamine (vitamin B1) serves an essential role as a co-factor of enzymes involved in cellular metabolic pathways (13-14); however, it cannot be synthesized de novo in mammalian cells and must be obtained through dietary and microbiota-generated sources. A recently published report demonstrated that SLC44A4 is involved in transport of the phosphorylated form of thiamine (thiamine pyrophosphate) produced by microbiota in the intestine (9). Such a functional role would be consistent with the expression we observed within normal tissues of the gastrointestinal tract, although thiamine pyrophosphate was not one of the substrates we tested for uptake.…”

Section: Discussionsupporting

confidence: 70%

“…Although this family of proteins is thought to be involved in choline transport, only SLC44A1 and SLC44A2 have been demonstrated to have choline transport activity (1-7). SLC44A4 has not been shown to be involved in choline transport, but it has been linked with acetylcholine synthesis and transport (8) as well as uptake of thiamine pyrophosphate, the phosphorylated form of vitamin B1 (9).…”

Section: Introductionmentioning

confidence: 99%

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The Discovery and Preclinical Development of ASG-5ME, an Antibody–Drug Conjugate Targeting SLC44A4-Positive Epithelial Tumors Including Pancreatic and Prostate Cancer

Mattie

Raitano

Morrison

et al. 2016

Molecular Cancer Therapeutics

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Here, we report the development of an antibody-drug conjugate, ASG-5ME, which targets the solute carrier receptor SLC44A4. SLC44A4 is a member of a family of putative choline transporters that we show to be markedly upregulated in a variety of epithelial tumors, most notably prostate and pancreatic cancer. SLC44A4 is normally expressed on the apical surface of secretory epithelial cells, but in cancer we show expression is not restricted to the luminal surface in advanced and undifferentiated tumors. ASG-5ME consists of a human IgG2 anti-SLC44A4 antibody conjugated through a cleavable linker to the microtubule-disrupting agent monomethylauristatin E. It has potent antitumor activity in both cell line-and patient-derived xenograft models of pancreatic and prostate cancers. Combination studies with ASG-5ME and nab-paclitaxel demonstrated combination effect in both pancreatic and prostate tumor models. Altogether, the data presented here suggest that ASG-5ME may have the potential to offer a new therapeutic option for the treatment of pancreatic and prostate cancers. Mol Cancer Ther; 15(11); 2679-87. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

The Discovery and Preclinical Development of ASG-5ME, an Antibody–Drug Conjugate Targeting SLC44A4-Positive Epithelial Tumors Including Pancreatic and Prostate Cancer

Mattie

Raitano

Morrison

et al. 2016

Molecular Cancer Therapeutics

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“…2e). Low thiamine blood levels have been linked to complications of T1DM 48 and colonic uptake transporters of thiamine have been described 49 . However, the observed patterns in transcript abundances of thiazole synthase and plasma thiamine levels were not correlated in the small subset of individuals who did not take thiamine supplements, precluding any conclusions (Supplementary Section 18 and Supplementary Fig.…”

Section: Human Protein Excretion In T1dm and Microbial Functionsmentioning

confidence: 99%

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

et al. 2016

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The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease remains challenging. Here, we present an integrative approach to resolve the taxonomic and functional attributes of gastrointestinal microbiota at the metagenomic, metatranscriptomic and metaproteomic levels. We apply our methods to samples from four families with multiple cases of type 1 diabetes mellitus (T1DM). Analysis of intra-and inter-individual variation demonstrates that family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. In the context of T1DM, consistent taxonomic differences were absent across families, but certain human exocrine pancreatic proteins were found at lower levels. The associated microbial functional signatures were linked to metabolic traits in distinct taxa. The methodologies and results provide a foundation for future large-scale integrated multi-omic analyses of the gastrointestinal microbiome in the context of host-microbe interactions in human health and disease.

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“…Bacterial sources of thiamine refer to the vitamin that is generated by the colonic microbiota, which exists in the free and the diphosphorylated (TPP) forms (2,7,8,15). Studies from our laboratory have shown that both forms of the vitamin can be captured by colonic epithelial cells (13,14,23). Free thiamine can be taken up by colonocytes via a specific and highly efficient process with characteristics that closely resemble those for the thiamine uptake process occurring in the small intestine (reviewed in Refs.…”

mentioning

confidence: 98%

Regulation of basal promoter activity of the human thiamine pyrophosphate transporter SLC44A4 in human intestinal epithelial cells

Nabokina

Ramos

Valle

et al. 2015

American Journal of Physiology-Cell Physiology

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Microbiota of the large intestine synthesize considerable amount of vitamin B1 in the form of thiamine pyrophosphate (TPP). There is a specific high-affinity regulated carrier-mediated uptake system for TPP in human colonocytes (product of the SLC44A4 gene). The mechanisms of regulation of SLC44A4 gene expression are currently unknown. In this study, we characterized the SLC44A4 minimal promoter region and identified transcription factors important for basal promoter activity in colonic epithelial cells. The 5'-regulatory region of the SLC44A4 gene (1,022 bp) was cloned and showed promoter activity upon transient transfection into human colonic epithelial NCM460 cells. With the use of a series of 5'- and 3'-deletion luciferase reporter constructs, the minimal genomic region that required basal transcription of the SLC44A4 gene expression was mapped between nucleotides -178 and +88 (using the distal transcriptional start site as +1). Mutational analysis performed on putative cis-regulatory elements established the involvement of ETS/ELF3 [E26 transformation-specific sequence (ETS) proteins], cAMP-responsive element (CRE), and SP1/GC-box sequence motifs in basal SLC44A4 promoter activity. By means of EMSA, binding of ELF3 and CRE-binding protein-1 (CREB-1) transcription factors to the SLC44A4 minimal promoter was shown. Contribution of CREB into SLC44A4 promoter activity was confirmed using NCM460 cells overexpressing CREB. We also found high expression of ELF3 and CREB-1 in colonic (NCM460) compared with noncolonic (ARPE19) cells, suggesting their possible contribution to colon-specific pattern of SLC44A4 expression. This study represents the first characterization of the SLC44A4 promoter and reports the importance of both ELF3 and CREB-1 transcription factors in the maintenance of basal promoter activity in colonic epithelial cells.

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Molecular Identification and Functional Characterization of the Human Colonic Thiamine Pyrophosphate Transporter

Cited by 66 publications

References 33 publications

The Discovery and Preclinical Development of ASG-5ME, an Antibody–Drug Conjugate Targeting SLC44A4-Positive Epithelial Tumors Including Pancreatic and Prostate Cancer

The Discovery and Preclinical Development of ASG-5ME, an Antibody–Drug Conjugate Targeting SLC44A4-Positive Epithelial Tumors Including Pancreatic and Prostate Cancer

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

Regulation of basal promoter activity of the human thiamine pyrophosphate transporter SLC44A4 in human intestinal epithelial cells

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