4q28.3. View the map and FISH BAC clones (data from UCSC genome browser).
SLC7A11: 12 exons, 71,737bp , chr4:139,449,092-139,520,828.
The figure below shows the structure of the SLC7A11 gene (data from UCSC genome browser).
Search the 5'UTR and 1kb upstream regions (seq1=human SLC7A11, seq2=mouse Slc7a11) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here). Two amino acid response elements (AAREs), each located in the opposite direction with an intervening sequence, were found in the 5'-flanking region of the mouse xCT gene (Sato, et al (2004)). The 5'-deletion analysis revealed that the sequence between -116 and -82 is essential for the basal expression and the sequence between -226 and -116 containing EpRE-1 is essential in response to diethyl maleate(Sasaki, et al).
Tissue specificity: Widely expressed. It is expressed in Muller and retinal pigment epithelial cells, and a retinal ganglion cell line (RGC-5). Oxidative stress upregulates this transport system in RGC-5 cells (Dun, et al). Northern blot analysis demonstrated that the expression of both xCT and 4F2hc was significantly enhanced by oxygen. (Sato, et al (2000)).
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
xCT (NP_055146): 501aa, UniProtKB/Swiss-Prot entry Q9UPY5.
Synonym: Amino acid transport system xc-, Calcium channel blocker resistance protein CCBR1, Cystine/glutamate transporter, solute carrier family 7 (cationic amino acid transporter, y+ system) member 11
|Protein||NP_036120 (502aa)||XP_227120 (502aa)||XP_540941 (551aa)||XP_426289 (580aa)|
|Identities||89% /500aa||87% /500aa||92% /482aa||68% /578aa|
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
(1) Domains predicted by SMART:
AA_permease: 48- 479
(2) Transmembrane domains predicted by SOSUI:
This amino acid sequence is of a MEMBRANE PROTEIN which have 13 transmembrane helices.
|No.||N terminal||transmembrane region||C terminal||type||length|
(3) Graphic view of InterPro domain structure.
(1) Predicted results by ScanProsite:
a) N-glycosylation site: 314 to 317 NFSL.
b) cAMP- and cGMP-dependent protein kinase phosphorylation site: 42 to 45 RKVT; 361 to 364 RKHT.
c) Protein kinase C phosphorylation site: 65 to 67 SPK; 103 to 105 TIK; 187 to 189 SAR; 226 to 228 SGR; 308 to 310 SER; 481 to 483 SEK.
d) Casein kinase II phosphorylation site: 96 to 99 SYAE; 226 to 229 SGRD; 306 to 309 TFSE.
e) N-myristoylation site: 9 sites.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) 11 tentative TMs, membrane topology: type 3a
c) KDEL ER retention motif in C-terminus: none
d) ER membrane retention signals:
XXRR-like motif in the N-terminus: VRKP; KKXX-like motif in the C-terminus: EEDK
e) VAC possible vacuolar targeting motif: none
f) Actinin-type actin-binding motif: type 1: none; type 2: none
g) Prenylation motif: none
h) memYQRL transport motif from cell surface to Golgi: none
i) Tyrosines in the tail: none
j) Dileucine motif in the tail: none
(1)ModBase predicted comparative 3D structure of Q9UPY5 from UCSC Genome Sorter.
From left to right: Front, Top, and Side views of predicted protein.
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=55,423Da, pI=9.29 (NP_055146).
(1) Biological process: amino acid transport.
(2) Pheomelanin production.
(3) Oxidative stress.
(4) Belongs to the amino acid-polyamine-organocation (APC) superfamily. L-type amino acid transporter (LAT) (TC 2.A.3.8) family.
Integral membrane protein. Transport system xc- was found in plasma membrane of cultured mammalian cells (Sato, et al (1999)).
SLC7A11 (xCT), together with SLC3A2 (4F2hc, or CD98) linked by a disulfide bond at residue C158, encodes the heterodimeric amino acid transport system x(c)(-), which mediates cystine-glutamate exchange and thereby regulates intracellular glutathione levels. System x(c)- activity is important to maintain both intracellular glutathione levels and the redox balance between cystine and cysteine in the extracellular milieu. rBAT can replace 4F2hc in the expression of the activity of system x(c)(-) (Wang, et al).
In mouse NIH3T3 cells, the activity of system x(c)(-) and xCT mRNA is induced not only by deprivation of cystine but also by deprivation of other amino acids via a genomic cis-element termed amino acid response element (AARE) (Sato, et al (2004)). Overexpression of Nrf-2 in astrocytes specifically increases expression of the xCT cystine/glutamate antiporter and other thiol synthesis-related proteins, to promote cell survival (Qiang, et al). Cys(327) is a functionally important residue accessible to the aqueous extracellular environment and is structurally linked to the permeation pathway and/or the substrate binding site (Jimenez-Vidal, et al).
A CD44 variant (CD44v) interacts with xCT and controls the intracellular level of reduced glutathione (GSH). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38(MAPK), a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21(CIP1/WAF1)(Ishimoto, et al). xCT has been identified as a receptor mediating KSHV cell fusion (Kaleeba, et al).
miR-26b, which is down-regulated in human breast cancer specimens and cell lines, impairs viability and triggers apoptosis of human breast cancer MCF7 cells. SLC7A11 is identified as a direct target of miR-26b and its expression is remarkably increased in both breast cancer cell lines and clinical samples (Liu, et al).
System x(c)(-) is a sodium-independent, high-affinity transporter of anionic amino acids with high specificity for anionic form of cystine and glutamate. Chintala, et al have reported that Slc7a11 regulates the pheomelanin production and cell proliferation. In melanosomes, dopaquinone reacts with cysteine to yield cysteinldopa, which is a precursor of pheomelanin. Cysteine is a component of the tripeptide glutathione. Glutathione metabolism pathway is described in KEGG Pathways.
No mutation has been reported in 32 human HPS patients who lack mutations in the seven known HPS genes (Chintala, et al).
SNPs deposited in dbSNP.
SLC7A11 is described in OMIM 607933.
Cystine uptake in human cancer cells is largely mediated by system Xc. xCT is relatively highly expressed in lung, colon, and central nervous system cancer cells (Huang, et al). Modulation of xCT activity is possiblely untilized in cancer therapy. Pharmacologic inhibition of system Xc remarkably inhibits the proliferation of several types of cancer cells, including lymphoma, glioma, prostate and breast cancer (Chung, et al; Doxsee, et al; Gout, et al; Narang, et al). This is thought be mediated by the depletion of GSH, which results in an increase of reactive oxygen species (ROS), and ultimately leads to caspase-dependent apoptosis (Doxsee, et al; Sakakura, et al). The apoptosis is likely mediated by c-Jun N-terminal kinase (JNK) activation. The JNK activation triggers both a caspase-dependent (caspases-9 and -3) and an ER stress-mediated (eIF2 and CHOP) pathway to induce apoptosis (Qiao, et al). In the absence of phospho-eIF2alpha, xCT expression is down-regulated that is mediated by nuclear factor ATF4, implicating the role eIF2alpha-ATF4-xCT module in neurodegeneration (Lewerenz, et al).
Disruption of xCT enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion in an esophageal cancer cell line, KYSE150. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and beta-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of beta-catenin transcriptional activity. Upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation (Chen, et al). Savaskan et al show that genetic or pharmacological inhibition of the glutamate transporter Xc system in gliomas leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. xCT deficiency causes unremitting inflammation because of the impaired survival of activated macrophages at the inflammatory site (Nabeyama, et al).
Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) is the causative agent of Kaposi's sarcoma and other lymphoproliferative syndromes often associated with HIV/AIDS. xCT mediates the entry of KSHV which implicates its involvement in the infectious process of this pathogen (Kaleeba, et al; Veettil, et al (2006); Rappocciolo, et al). KSHV interacts with functionally related integrins (alphaVbeta3, alpha3beta1, and alphaVbeta5) and CD98/xCT molecules in a temporal fashion to form a multimolecular complex during the early stages of endothelial cell infection, probably mediating multiple roles in entry, signal transduction, and viral-gene expression (Veettil, et al (2008)). xCT was overexpressed in KS tissues and HHV-8-positive BCBL-1 cells. 14-3-3beta is a downstream effector of xCT in KS to mediate the cell proliferation (Zeng, et al). KSHV-encoded microRNAs (KSHV miRNAs) upregulate xCT expression by macrophages and endothelial cells, largely through miR-K12-11 suppression of BACH-1-a negative regulator of transcription recognizing antioxidant response elements within gene promoters (Qin, et al).