<i>Slc7a11</i>
            gene controls production of pheomelanin pigment and proliferation of cultured cells

Chintala, Sreenivasulu; Li, Wei; Lamoreux, M. Lynn; Ito, Shosuke; Wakamatsu, Kazumasa; Sviderskaya, Elena V.; Bennett, Dorothy C.; Park, Young‐Mee; Gahl, William A.; Huizing, Marjan; Spritz, Richard A.; Ben, Songtao; Novak, Edward K.; Tan, Jian; Swank, Richard T.

doi:10.1073/pnas.0502856102

Cited by 190 publications

(196 citation statements)

References 27 publications

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“…2003; Chintala et al. 2005). None of these, however, give rise to the cream‐colored coat observed in several dog and some cattle breeds (Guibert et al.…”

Section: Discussionmentioning

confidence: 99%

Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration in Antarctic fur seals

Peters

Humble

Kröcker

et al. 2016

Ecology and Evolution

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Although the genetic basis of color variation has been extensively studied in humans and domestic animals, the genetic polymorphisms responsible for different color morphs remain to be elucidated in many wild vertebrate species. For example, hypopigmentation has been observed in numerous marine mammal species but the underlying mutations have not been identified. A particularly compelling candidate gene for explaining color polymorphism is the melanocortin 1 receptor (MC1R), which plays a key role in the regulation of pigment production. We therefore used Antarctic fur seals (Arctocephalus gazella) as a highly tractable marine mammal system with which to test for an association between nucleotide variation at the MC1R and melanin‐based coat color phenotypes. By sequencing 70 wild‐type individuals with dark‐colored coats and 26 hypopigmented individuals with cream‐colored coats, we identified a nonsynonymous mutation that results in the substitution of serine with phenylalanine at an evolutionarily highly conserved structural domain. All of the hypopigmented individuals were homozygous for the allele coding for phenylalanine, consistent with a recessive loss‐of‐function allele. In order to test for cryptic population structure, which can generate artefactual associations, and to evaluate whether homozygosity at the MC1R could be indicative of low genome‐wide heterozygosity, we also genotyped all of the individuals at 50 polymorphic microsatellite loci. We were unable to detect any population structure and also found that wild‐type and hypopigmented individuals did not differ significantly in their standardized multilocus heterozygosity. Such a lack of association implies that hypopigmented individuals are unlikely to suffer disproportionately from inbreeding depression, and hence, we have no reason to believe that they are at a selective disadvantage in the wider population.

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“…2003; Chintala et al. 2005). None of these, however, give rise to the cream‐colored coat observed in several dog and some cattle breeds (Guibert et al.…”

Section: Discussionmentioning

confidence: 99%

Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration in Antarctic fur seals

Peters

Humble

Kröcker

et al. 2016

Ecology and Evolution

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“…In our earlier studies, we demonstrated the inhibition of cell proliferation in sut/sut (sut) melanocytes and fibroblasts, in which function of xCT is null due to a replacement of its C terminus (Chintala et al, 2005). Our recent results have further shown that the death of sut cells is likely through apoptosis mediated by JNK activation (Qiao et al, 2008).…”

Section: Introductionmentioning

confidence: 90%

“…The melanocyte line from xCT À/À mice (sut) and the mela a cell line from wild-type mice were established in Dr Dorothy Bennett's laboratory (University of London) and cultured as described (Chintala et al, 2005). The medium for both xCT þ / þ and xCT À/À melanocytes was supplemented with b-mercaptoethanol (Sigma-Aldrich, St Louis, MO, USA).…”

Section: Cell Culturementioning

confidence: 99%

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

et al. 2008

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xCT, the functional subunit of the cystine/glutamate transporter xc-system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role of xCT in tumor metastasis remains largely unknown. In this study, both xCT þ / þ and xCT À/À melanocytes were used to evaluate the role of xCT in adhesion. xCT activity was suppressed by an inhibitor, sulfasalazine (SASP), or by xCT siRNA in an esophageal cancer cell line, KYSE150. We found that disruption of xCT enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and b-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of b-catenin transcriptional activity. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation. These results first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy.

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“…An abnormal accumulation of tyrosinase (possibly in the trans-Golgi network) was found in the sut melanocyte, showing an anomalous trafficking of tyrosinase in the absence of cysteine. This abnormality does not seem to have any affect on eumelanin production (Chintala et al 2005). SLC45A2 is also a 12-transmembrane transport protein but it is still unclear which molecules it transports (Fukamachi et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies it has been suggested that Silver may block the incorporation of sulfhydryls in pheomelanin since ultrastructural studies showed that sparsely melanized pheomelanosomes were coincident with histochemically sulfhydryl-negative melanocytes (Brumbaugh 1971). The subtle gray (sut) mouse has a mutation in the Slc7a11 gene encoding the cystine/glutamate exchanger xCT (Chintala et al 2005). xCT has 12 predicted transmembrane regions and the cystine taken up by the cell via xCT is rapidly reduced to cysteine (Sato et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail

et al. 2007

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S *S (Silver), S *N (wild type/gold), and S *AL (sex-linked imperfect albinism) form a series of alleles at the S (Silver) locus on chicken (Gallus gallus) chromosome Z. Similarly, sex-linked imperfect albinism (AL*A) is the bottom recessive allele at the orthologous AL locus in Japanese quail (Coturnix japonica). The solute carrier family 45, member 2, protein (SLC45A2), previously denoted membrane-associated transporter protein (MATP), has an important role in vesicle sorting in the melanocytes. Here we report five SLC45A2 mutations. The 106delT mutation in the chicken S *AL allele results in a frameshift and a premature stop codon and the corresponding mRNA appears to be degraded by nonsense-mediated mRNA decay. A splice-site mutation in the Japanese quail AL*A allele causes in-frame skipping of exon 4. Two independent missense mutations (Tyr277Cys and Leu347Met) were associated with the Silver allele in chicken. The functional significance of the former mutation, associated only with Silver in White Leghorn, is unclear. Ala72Asp was associated with the cinnamon allele (AL*C ) in the Japanese quail. The most interesting feature concerning the SLC45A2 variants documented in this study is the specific inhibition of expression of red pheomelanin in Silver chickens. This phenotypic effect cannot be explained on the basis of the current, incomplete, understanding of SLC45A2 function. It is an enigma why recessive null mutations at this locus cause an almost complete absence of both eumelanin and pheomelanin whereas some missense mutations are dominant and cause a specific inhibition of pheomelanin production.

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Slc7a11 gene controls production of pheomelanin pigment and proliferation of cultured cells

Cited by 190 publications

References 27 publications

Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration in Antarctic fur seals

Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration in Antarctic fur seals

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail

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