Alternative titles; symbols
HGNC Approved Gene Symbol: SLC5A8
Cytogenetic location: 12q23.1-q23.2 Genomic coordinates (GRCh38) : 12:101,155,493-101,210,238 (from NCBI)
SLC5A8 has been shown to transport iodide by a passive mechanism (Rodriguez et al., 2002) and monocarboxylates and short-chain fatty acids by a sodium-coupled mechanism (Gopal et al., 2004). In kidney, SLC5A8 functions as a high-affinity sodium-coupled lactate transporter involved in reabsorption of lactate and maintenance of blood lactate levels (Thangaraju et al., 2006).
By searching EST databases for sequences similar to NIS (SLC5A5; 601843), followed by RT-PCR and RACE of a kidney cDNA library, Rodriguez et al. (2002) cloned SLC5A8, which they designated AIT. The deduced 610-amino acid protein contains 13 putative transmembrane domains, 2 potential N-glycosylation sites, and several sites for serine and threonine phosphorylation. AIT shares 46% amino acid identity with NIS. RT-PCR showed that expression of AIT was 10 times higher in thyroid than in kidney. Immunolocalization of AIT in thyroid detected apical staining of thyrocytes. Staining was heterogeneous between follicles, and inside any given follicle, only half of the thyrocytes were stained.
To identify tumor suppressor genes and/or identify genes targeted for methylation in human colon cancer, Li et al. (2003) performed restriction landmark genome scanning (RLGS) analysis of 12 colon cancer cell lines. They found that 1 spot among 1,231 unselected CpG islands visualized by RLGS was absent and presumptively methylated in 11 of the 12 colon cancer cell lines. Li et al. (2003) cloned a 510-bp genomic fragment surrounding the NotI site represented by that spot and showed that it corresponded to genomic sequence on chromosome 12. By EST database analysis and RT-PCR using normal colon mucosa RNA, they isolated the SLC5A8 gene and determined that the NotI site was located within its first exon. The SLC5A8 transcript includes an in-frame TAA stop codon 5-prime to the presumptive ATG start codon, which is imbedded within a GCCATGG sequence that conforms to a good Kozak sequence. The predicted 610-amino acid SLC5A8 protein shares 48% homology with SLC5A5 and 43% homology with SLC5A6 (604024), and it shows structural features of a sodium-iodide symporter. It shares 77% identity with mouse Slc5a8. RT-PCR analysis detected expression of SLC5A8 in normal colon mucosa, kidney, lung, esophagus, small bowel, stomach, thyroid, and uterus. Expression was highest in kidney.
By analyzing iodide transport in transfected COS-7 and Chinese hamster ovary cells, Rodriguez et al. (2002) determined that AIT catalyzes passive iodide transport.
By functional analysis using Xenopus oocytes, Li et al. (2003) showed that SLC5A8 encodes a sodium transporter.
Li et al. (2003) identified SLC5A8 as a candidate tumor suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. They found that, in normal colon mucosa, SLC5A8 exon 1 was unmethylated and SLC5A8 transcript was expressed. In contrast, SLC5A8 exon 1 was aberrantly methylated in 59% of primary colon cancers and 52% of colon cancer cell lines tested. Cells in which SLC5A8 exon 1 was methylated were uniformly silenced for SLC5A8 expression, but reactivated expression was achieved by treatment with a demethylating drug, 5-azacytidine. Transfection of SLC5A8 suppressed colony growth in each of 3 SLC5A8-deficient cell lines, but showed no suppressive effect in any of 3 SLC5A8-proficient cell lines. Li et al. (2003) suggested that SLC5A8 methylation might be a high-quality marker of colon cancer presence. Because aberrantly methylated genomic DNA from specific loci can be detected in the serum of some cancer patients, they characterized the level of SLC5A8 methylation in ethanol-precipitable DNA prepared from the serum of colon cancer patients. SLC5A8 methylation was totally undetectable in DNA extracted from each of 13 serum samples from individuals with colon cancers in which SLC5A8 assayed as unmethylated. In contrast, SLC5A8 methylation was detectable in serum DNA from 4 of 10 patients in whom the underlying colon cancer assayed as SLC5A8-methylated.
Following expression in mammalian cells and Xenopus oocytes, Gopal et al. (2004) demonstrated that mouse Slc5a8 mediated Na(+)-coupled electrogenic transport of lactate, pyruvate, and short-chain fatty acids, such as acetate, propionate, and butyrate. The Na(+)/fatty acid stoichiometry varied depending on the fatty acid substrate (2:1 for lactate and 4:1 for propionate). The phenomenon of variable Na(+)/substrate stoichiometry was also found with human SLC5A8. In situ hybridization of sagittal sections of mouse kidney demonstrated abundant expression of Slc5a8 in both the cortex and medulla. Brush border membrane vesicles prepared from rabbit kidney were able to transport lactate in a Na(+)-coupled manner. The transport process exhibited the overshoot phenomenon, indicating uphill lactate transport in response to the transmembrane Na(+) gradient. The Na(+)-coupled lactate transport in these membrane vesicles could be inhibited by short-chain fatty acids. Gopal et al. (2004) concluded that SLC5A8 plays a role in the active renal reabsorption of lactate.
Porra et al. (2005) examined the expression pattern of SLC5A8 in normal human thyrocytes and in 50 hypofunctioning tumors. SLC5A8 expression was studied at the transcript level and compared with that of SLC26A4 (605646) and SLC5A5. SLC5A8 expression, unlike that of SLC5A5 and SLC26A4, was not regulated by TSH (see 188540) in normal human thyrocytes in culture and was not related to the functional state of thyroid tissue; toxic adenomas and adjacent resting tissues exhibited the same SLC5A8 transcript content. SLC5A8 expression was selectively downregulated (40-fold) in papillary thyroid carcinomas (PTCs; see 188550) of classical form. Methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classical PTCs and in about 20% of other PTCs. In a series of 52 classical PTCs, a low SLC5A8 expression was highly significantly associated with the presence of the BRAF 1799T-A mutation (V600E; 164757.0001). Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classical PTC subtype of thyroid carcinomas.
Thangaraju et al. (2006) found that the renal expression of Slc5a8 and Slc5a12 (612455) was reduced in Cebpd (116898) +/- mice and was almost completely ablated in Cebpd -/- mice. Expression of other renal transporters, including the uric acid transporter Urat1 (SLC22A12; 607096), remained normal in Cebpd -/- mice, and expression of Slc5a8 and Slc5a12 in brain and intestine was unaffected by Cebpd deletion. Reporter gene assays using the promoter regions of human SLC5A8 and SLC5A12 confirmed that CEBPD induced expression of these transporters. Ablation of Slc5a8 and Slc5a12 in Cebpd -/- mouse kidney was accompanied by a marked increase in urinary excretion of lactate, as well as reduced blood levels of lactate. In addition, urinary excretion of urate was significantly elevated in Cebpd -/- mice, even though expression of Urat1 was not altered. Thangaraju et al. (2006) hypothesized that lactate reabsorption by SLC5A8 and SLC5A12 is coupled to urate reabsorption by URAT1 at the proximal tubule apical membrane.
Dichloroacetate (DCA) is a potential anticancer drug that inhibits pyruvate dehydrogenase kinase (see PKD1; 602524) and induces apoptosis through activation of mitochondrial pyruvate oxidation. Babu et al. (2011) found that SLC5A8 transported DCA in a sodium-dependent manner and that several cancer cell lines were resistant to DCA due to epigenetic downregulation of SLC5A8. Reexpression of SLC5A8 in several human cancer cell lines induced DCA sensitivity, resulting in DCA-dependent apoptosis. DCA did not induce apoptosis in cancer cells lacking SLC5A8 expression or in normal cells expressing endogenous SLC5A8.
Li et al. (2003) determined that the SLC5A8 gene contains 15 exons.
By genomic sequence analysis, Rodriguez et al. (2002) mapped the SLC5A8 gene to chromosome 12q23. Li et al. (2003) mapped the SLC5A8 gene to chromosome 12q22-q23 by genomic sequence analysis.
Babu, E., Ramachandran, S., CoothanKandaswamy, V., Elangovan, S., Prasad, P. D., Ganapathy, V., Thangaraju, M. Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate. Oncogene 30: 4026-4037, 2011. [PubMed: 21499304] [Full Text: https://doi.org/10.1038/onc.2011.113]
Gopal, E., Fei, Y.-J., Sugawara, M., Miyauchi, S., Zhuang, L., Martin, P., Smith, S. B., Prasad, P. D., Ganapathy, V. Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate. J. Biol. Chem. 279: 44522-44532, 2004. [PubMed: 15322102] [Full Text: https://doi.org/10.1074/jbc.M405365200]
Li, H., Myeroff, L., Smiraglia, D., Romero, M. F., Pretlow, T. P., Kasturi, L., Lutterbaugh, J., Rerko, R. M., Casey, G., Issa, J.-P., Willis, J., Willson, J. K. V., Plass, C., Markowitz, S. D. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc. Nat. Acad. Sci. 100: 8412-8417, 2003. [PubMed: 12829793] [Full Text: https://doi.org/10.1073/pnas.1430846100]
Porra, V., Ferraro-Peyret, C., Durand, C., Selmi-Ruby, S., Giroud, H., Berger-Dutrieux, N., Decaussin, M., Peix, J.-L., Bournaud, C., Orgiazzi, J., Borson-Chazot, F., Dante, R., Rousset, B. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J. Clin. Endocr. Metab. 90: 3028-3035, 2005. [PubMed: 15687339] [Full Text: https://doi.org/10.1210/jc.2004-1394]
Rodriguez, A.-M., Perron, B., Lacroix, L., Caillou, B., Leblanc, G., Schlumberger, M., Bidart, J.-M., Pourcher, T. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J. Clin. Endocr. Metab. 87: 3500-3503, 2002. [PubMed: 12107270] [Full Text: https://doi.org/10.1210/jcem.87.7.8797]
Thangaraju, M., Ananth, S., Martin, P. M., Roon, P., Smith, S. B., Sterneck, E., Prasad, P. D., Ganapathy, V. c/ebp-delta null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney. J. Biol. Chem. 281: 26769-26773, 2006. [PubMed: 16873376] [Full Text: https://doi.org/10.1074/jbc.C600189200]