全周 (9AM - 6PM)

我们和你在一起

Extra info thumb
SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 11; SLC7A11

SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 11; SLC7A11

Alternative titles; symbolsSYSTEM Xc(-) TRANSPORTER-RELATED PROTEIN; XCTHGNC Approved Gene Symbol: SLC7A11Cytogenetic location: 4q28.3 Genomic coordinates (G...

Alternative titles; symbols

  • SYSTEM Xc(-) TRANSPORTER-RELATED PROTEIN; XCT

HGNC Approved Gene Symbol: SLC7A11

Cytogenetic location: 4q28.3 Genomic coordinates (GRCh38): 4:138,164,096-138,242,348 (from NCBI)

▼ Description

SLC7A11 is a member of a heteromeric Na(+)-independent anionic amino acid transport system highly specific for cystine and glutamate. In this system, designated system Xc(-), the anionic form of cystine is transported in exchange for glutamate (summary by Sato et al., 1999).

▼ Cloning and Expression

By expression cloning for cystine uptake in Xenopus oocytes, Sato et al. (1999) cloned mouse Slc1a11, which they designated xCT. The deduced 502-amino acid protein had an apparent molecular mass of about 40 kD following in vitro translation in canine pancreatic microsomes. Mouse xCT was found to be extremely hydrophobic and was predicted to contain 12 membrane-spanning domains. Northern blot analysis of activated mouse macrophages detected transcripts of 12, 3.5, and 2.5 kb. Northern blot analysis of mouse tissues detected expression in brain, but not in other organs tested.

Kaleeba and Berger (2006) identified human XCT by functional cDNA selection for a receptor mediating Kaposi sarcoma-associated herpesvirus (KSHV; see 148000) cell fusion. The 501-amino acid XCT protein has 12 transmembrane domains and cytoplasmic N and C termini.

▼ Gene Function

Sato et al. (1999) determined that uptake of cystine in Xenopus oocytes increased substantially when mouse xCT cRNA was coinjected with 4f2hc (SLC3A2; 158070) cRNA. Injection of either cRNA alone did not enhance uptake of cystine and glutamate. Expression of xCT was not visible in RNA from freshly prepared mouse macrophages, but it was enhanced in macrophages activated with lipopolysaccharide or diethyl maleate.

Kaleeba and Berger (2006) identified XCT as the predominant mediator of KSHV fusion and entry permissiveness in several cell lines from different species and tissue lineages. Antisera against XCT extracellular regions, but not most intracellular regions, inhibited KSHV entry in transfected and naturally permissive cell lines. RT-PCR and flow cytometric analysis showed that XCT mRNA and protein levels correlated with cell line KSHV entry permissiveness. Kaleeba and Berger (2006) noted that intracellular glutathione levels, which are maintained by XCT-mediated cystine uptake, are depleted during human immunodeficiency virus (HIV) disease. They proposed that HIV coinfection may foster Kaposi sarcoma by both immunosuppression and KSHV receptor upregulation.

Savaskan et al. (2008) found that human primary gliomas (137800) showed increased expression of the SLC7A11 gene that was associated with increased glutamate secretion compared to normal brain tissue. Further studies suggested that gliomas secrete glutamate via XCT channels, thereby causing neuronal cell death. Genetic or pharmacologic inhibition of Xct in rats with gliomas abrogated neurodegeneration, attenuated perifocal edema, and prolonged survival. These findings indicated a crucial role for XCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.

Jiang et al. (2015) showed that p53 (191170) inhibits cystine uptake and sensitizes cells to ferroptosis, a nonapoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p53(3KR), an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence, and apoptosis, fully retains the ability to regulate SLC7A11 expression and to induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice showed that these noncanonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2 (164785). Moreover, SLC7A11 is highly expressed in human tumors, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53(3KR)-mediated tumor growth suppression in xenograft models.

Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid ROS. Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. Badgley et al. (2020) showed that the import of oxidized cysteine (cystine) via system x(C)- is a critical dependency of pancreatic ductal adenocarcinoma (PDAC; see 260350). PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, downregulate ferroptosis. Studying genetically engineered mice, Badgley et al. (2020) found that the deletion of a system x(C)- subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

▼ Mapping

The International Radiation Hybrid Mapping Consortium mapped the SLC7A11 gene to chromosome 4 (D4S3103).

Tags: 4q28.3