• Molecules and Cells
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• 제40권10호
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• pp.761-772
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• 2017

Glioblastoma is the most frequent and most aggressive brain tumor in adults. Solute carrier family 8 member 2 (SLC8A2) is only expressed in normal brain, but not present in other human normal tissues or in gliomas. Therefore, we hypothesized that SLC8A2 might be a glioma tumor suppressor gene and detected the role of SLC8A2 in glioblastoma and explored the underlying molecular mechanism. The glioblastoma U87MG cells stably transfected with the lentivirus plasmid containg SLC8A2 (U87MG-SLC8A2) and negative control (U87MG-NC) were constructed. In the present study, we found that the tumorigenicity of U87MG in nude mice was totally inhibited by SLC8A2. Overexpression of SLC8A2 had no effect on cell proliferation or cell cycle, but impaired the invasion and migration of U87MG cells, most likely through inactivating the extracellular signal-related kinases (ERK)1/2 signaling pathway, inhibiting the nuclear translocation and DNA binding activity of nuclear factor kappa B ($NF-{\kappa}B$), reducing the level of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA)-its receptor (uPAR) system (ERK1/2-$NF-{\kappa}B$-MMPs/uPA-uPAR), and altering the protein levels of epithelial to mesenchymal transitions (EMT)-associated proteins E-cardherin, vimentin and Snail. In addition, SLC8A2 inhibited the angiogenesis of U87MG cells, probably through combined inhibition of endothelium-dependent and endothelium-nondependent angiogenesis (vascular mimicry pattern). Totally, SLC8A2 serves as a tumor suppressor gene and inhibits invasion, angiogenesis and growth of glioblastoma.

• The Korean Journal of Physiology and Pharmacology
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• 제28권2호
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• pp.113-120
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• 2024

Solute carrier 40A1 (SLC40A1) encodes ferroportin, which is the only known transmembrane protein that exports elemental iron from mammalian cells and is essential for iron homeostasis. Mutations in SLC40A1 are associated with iron-overload disorders. In addition to ferroportin diseases, SLC40A1 expression is downregulated in various cancer types. Despite the clinical significance of the SLC40A1 transporter, only a few studies have investigated genetic variants in SLC40A1. The present study was performed to identify genetic variations in the SLC40A1 promoter and functionally characterize each variant using in vitro assays. We investigated four haplotypes and five variants in the SLC40A1 promoter. We observed that haplotype 3 (H3) had significantly lower promoter activity than H1, whereas the activity of H4 was significantly higher than that of H1. Luciferase activity of H2 was comparable to that of H1. In addition, four variants of SLC40A1, c.-1355G>C, c.-662C>T, c.-98G>C, and c.-8C>G, showed significantly increased luciferase activity compared to the wild type (WT), whereas c.-750G>A showed significantly decreased luciferase activity compared to the WT. Three transcription factors, cAMP response element-binding protein-1 (CREB-1), chicken ovalbumin upstream promoter transcription factor 1, and hepatic leukemia factor (HLF), were predicted to bind to the promoter regions of SLC40A1 near c.-662C>T, c.-98G>C, and c.-8C>G, respectively. Among these, CREB1 and HLF bound more strongly to the variant sequences than to the WT and functioned as activators of SLC40A1 transcription. Collectively, our findings indicate that the two SLC40A1 promoter haplotypes affect SLC40A1 transcription, which is regulated by CREB-1 and HLF.

• Reproductive and Developmental Biology
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• 제33권4호
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• pp.211-216
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• 2009

A cell frequently utilizes glucose as a fuel of energy and a major substrate of lipid and protein syntheses. A regulation of glucose movement into and out of the cells is precisely controlled by cooperative works of passive and sodium-dependent active processes. At least 13 glucose cotransporter (Slc2a, GLUT) isoforms involve in passive movement of glucose in cells. The efferent ductules (EDs) play in a number of important functions for maintenance of male fertility. In the present study, using real-time PCR analysis, we determined gene expression of five Slc2a isoforms in the EDs. In addition, we compared expression levels of these Slc2a isoforms according to postnatal development ages, 1 week, 2 weeks, 1 month, and 3 months. Results from the current study showed that expression of Slc2a1, Slc2a3, and Slc2a5 mRNAs reached the highest levels at 1 month of age, followed by a transient decrease at 3 months of age. In addition, the level of Slc2a4 mRNA reminded at steady until 1 month of age and was significantly reduced at 3 months of age, whereas the highest level of Slc2a 8 mRNA was detected at 2 weeks of age. Data from the present study indicate a differential expression of various Slc2a isoforms in the ED according to postnatal ages. Thus, it is believed that glucose movement through the epithelial cells in the ED would be regulated by the coordinated manner among Slc2a isoforms expressed at a given age.

• Clinical and Experimental Pediatrics
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• 제59권sup1호
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• pp.29-31
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• 2016

Glucose transport 1 (GLUT-1) deficiency is a rare syndrome caused by mutations in the glucose transporter 1 gene (SLC2A1) and is characterized by early-onset intractable epilepsy, delayed development, and movement disorder. De novo mutations and several hot spots in N34, G91, R126, R153, and R333 of exons 2, 3, 4, and 8 of SLC2A1 are associated with this condition. Seizures, one of the main clinical features of GLUT-1 deficiency, usually develop during infancy. Most patients experience brief and subtle myoclonic jerk and focal seizures that evolve into a mixture of different types of seizures, such as generalized tonic-clonic, absence, myoclonic, and complex partial seizures. Here, we describe the case of a patient with GLUT-1 deficiency who developed infantile spasms and showed delayed development at 6 months of age. She had intractable epilepsy despite receiving aggressive antiepileptic drug therapy, and underwent a metabolic workup. Cerebrospinal fluid (CSF) examination showed CSF-glucose-to-blood-glucose ratio of 0.38, with a normal lactate level. Bidirectional sequencing of SLC2A1 identified a missense mutation (c.1198C>T) at codon 400 (p.Arg400Cys) of exon 9.

• The Korean Journal of Physiology and Pharmacology
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• 제19권4호
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• pp.319-325
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• 2015

Among solute carrier proteins, the organic anion transporters (OATs) play an important role for the elimination or reabsorption of endogenous and exogenous negatively charged anionic compounds. Among OATs, SLC22A9 (hOAT7) transports estrone sulfate with high affinity. The net decrease of estrogen, especially in post-menopausal women induces rapid bone loss. The present study was performed to search the SNP within exon regions of SLC22A9 in Korean females with osteoporosis. Fifty healthy controls and 50 osteoporosis patients were screened for the genetic polymorphism in the coding region of SLC22A9 using GC-clamped PCR and denaturing gradient gel electrophoresis (DGGE). Six SNPs were found on the SLC22A9 gene from Korean women with/without osteoporosis. The SNPs were located as follows: two SNPs in the osteoporosis group (A645G and T1277C), three SNPs in the control group (G1449T, C1467T and C1487T) and one SNP in both the osteoporosis and control groups (G767A). The G767A, T1277C and C1487T SNPs result in an amino acid substitution, from synonymous vs nonsynonymous substitution arginine to glutamine (R256Q), phenylalanine to serine (F426S) and proline to leucine (P496L), respectively. The Km values and Vmax of the wild type, R256Q, P496L and F426S were 8.84, 8.87, 9.83 and $12.74{\mu}M$, and 1.97, 1.96, 2.06 and 1.55 pmol/oocyte/h, respectively. The present study demonstrates that the SLC22A9 variant F426S is causing inter-individual variation that is leading to the differences in transport of the steroid sulfate conjugate (estrone sulfate) and, therefore this could be used as a marker for certain disease including osteoporosis.

• 약학회지
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• 제54권1호
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• pp.49-54
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• 2010

SLC6A19 which reported as a neurotransmitter was composed of seven minisatellites. In previous our study, the minisatellites variants of SLC6A19-MS7 showed the susceptibility for hypertension. When this minisatellte sequences were analyzed using the bioinformatic tool, USF1 (upstream transcription factor 1) was found in this region as a putative transcription factor binding site. USF1 is binding with E-boxes which has a consensus sequence of CACGTG. USF1 is a ubiquitously expressed transcription factor and involved in the transcriptional control of many genes including the molecular pathogenesis of cardiovascular disease. Thus, we investigated that the putative functional relationship between the minisatellites variants and susceptibility for myocardial infarction. A case-control study was performed that compared genomic DNA from 400 controls and 225 cases with myocardial infarction. There were no significant differences observed in the overall allelic distribution of minisatellites between controls and cases, which indicates that this polymorphism is not responsible for myocardial infarction susceptibility. Hence, we analyzed the five different minisatellites alleles from this study and characterized 14 different repeats units (Unit1~Unit14). Then, we evaluated the DNA composition, phylogenic tree, and pairwise distances of its repeats. The variability of each repeats differed from 2.33% to 16%. The phylogenic trees for the four SLC6A19-MS7 minisatellites exhibited very different shapes in their braches and distances, and present most common 8 repeats allele was the longest 14 repeats allele. Therefore, this result may help to understand for the evolutional level of the length of minisatellites.

• Journal of Animal Science and Technology
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• 제51권6호
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• pp.493-502
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• 2009

Glucose is a major source of metabolic fuel and lipid and protein syntheses. Transport of glucose into the cell is regulated by an action of glucose transport.associated transporters, especially solute carriers 2A (Slc2a, protein symbol GLUT). The present study was focused on examination of mRNA expression of various Slc2a isoforms in the epididymis during postnatal development. Total RNAs isolated from different epididymal segments (caput, corpus, and caudal epididymis) were utilized for real-time polymerase chain reaction analyses. Results showed that Slc2a 1, 3, 4, 5, and 8 were expressed in the entire epididymal regions. In addition, the abundance of these Slc2a isoforms' transcripts was different within each epididymal regions. Moreover, the present study showed differential expression of these Slc2a isoforms among different epididymal segments according to postnatal ages. The current study suggests that glucose transport in the epididymis via various Slc2a isoforms would be necessary for maintenance of the epididymal functions.

• 한국수정란이식학회지
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• 제25권1호
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• pp.29-34
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• 2010

난포낭종은 소 번식 장애의 주요 원인 중의 하나이며, 다양한 유전자의 변화는 여러 세포와 조직 기능에 영향을 준다. 이러한 유전자 변화는 낭종성 난소에서도 나타날 수 있다. 이온 및 수송체와 관련된 유전자 변화가 한우의 난포낭종을 유발할 수 있을 것이라는 가설 하에 난포낭종성 난포에서 발현 변화를 보이는 유전자를 찾기 위하여 마이크로어레이 분석을 수행하였다. 마이크로어레이 분석 결과, 난포낭종성 난포에서 FGG와 LRP8이 증가하고, SLC44A4, SLC27A5, ANXA8 및 aquaporin 4는 감소하였다. 반정량적 역전사중합효소 연쇄 반응으로 마이크로어레이 분석 결과를 재확인하였다. 6개의 DEG 중 3개의 DEG(FGG, SLC44A4 및 aquaporin 4)는 마이크로어레이 분석 결과와 동일하게 증가와 감소를 보였다. 마이크로어레이와 역전사중합효소 반응에서 동일한 결과를 보이는 3개의 유전자 중 가장 크게 변화를 보인 섬유소원에 중점을 두고 연구를 수행하였다. 마이크로어레이와 역전사중합효소 연쇄 반응은 난포낭종성 난포에서 섬유소원 유전자 발현을 각각 8.4배와 1.7배 증가시켰다. 그러나 난포 및 과립층세포에서 섬유소원의 단백질 양은 웨스턴 블랏 분석으로 분석한 결과, 정상에 비하여 낭종에서 유의한 차이를 보이지 않았다. 본 연구에서 섬유소원은 유전자와 단백질 발현에 있어 상관관계는 보이지 않았지만 섬유소원 유전자는 정상 조직으로부터 난포낭종을 구별하는데 있어서 중요한 생물표지자가 될 수 있는 가능성을 제시한다.

• Childhood Kidney Diseases
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• 제16권2호
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• pp.121-125
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• 2012

Gitelman 증후군은 저칼륨혈증, 대사성 알칼리혈증, 고레닌혈증, 고알도스테론혈증, 저마그네슘혈증, 저칼슘뇨증, 고마그네슘뇨증과 정상 혈압을 특징으로 하는 상염색체 열성 유전성 세뇨관 질환이며 SLC12A3 유전자 돌연변이로 인해 원위 곱슬 세뇨관의 NCCT의 결함을 유발하여 초래된다. 환아는 Rolandic 간질 및 마제신으로 진단받고 본원 외래에서 주기적으로 진료받던 환아로 혈액검사에서 저칼륨혈증 및 대사성 알칼리혈증이 지속되었지만 정상 마그네슘혈증이 관찰되어 유전자검사를 통해 SLC12A3 유전자 돌연변이를 확인하였고 Gitelman 증후군으로 진단한 증례를 경험하였기에 보고하는 바이다.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• 제25권2호
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• pp.82-88
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• 2014

Objectives : The aim of our study was to investigate association of norepinephrine transporter gene (SLC6A2) polymorphism and side effects of osmotic-release oral system methylphenidate (OROS MPH) in children with attention-deficit hyperactivity disorder (ADHD). Methods : We recruited drug naive children with ADHD (N=97). We administered OROS MPH by tolerable dosage. At week 8 of treatment, parents completed the Barkley's side effect rating scale. We analyzed two SLC6A2 single nucleotide polymorphisms (SNPs), rs192303 and rs3785143, with blood of subjects. We compared the frequency and severity of each side effect among SLC6A2 genotypes of 2 SNPs. Results : In the analysis of frequency of each side effect, irritability differed according to rs192303 and rs3785143 genotype. In comparisons of severity, talking less and disinterest differed according to rs192303 genotype. In the case of rs3785143, severities of disinterest and irritability were involved with genotype. Conclusion : Side effects of OROS MPH showed an association with SLC6A2 genotype.