NCKX5, a Natural Regulator of Human Skin Colour Variation, Regulates the Expression of Key Pigment Genes MC1R and Alpha-MSH and Alters Cholesterol Homeostasis in Normal Human Melanocytes

Wilson, Stephen W.; Ginger, Rebecca S.; Dadd, Tony; Gunn, David; Lim, Fei Ling; Sawicka, Magdalena; Sandel, Melanie; Schnetkamp, Paul P. M.; Green, Martin R.

doi:10.1007/978-1-4614-4756-6_9

Cited by 18 publications

(17 citation statements)

References 47 publications

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“…α-MSH plays important roles in melanocyte growth and melanin production via cell surface receptor activation51. α-MSH has been also identified as a potent anti-inflammatory in various tissues including the skin.…”

Section: Discussionmentioning

confidence: 99%

Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

Wan

Lin²,

Zhang

et al. 2017

Int. J. Biol. Sci.

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Vitiligo is a skin depigmentation disorder with an increasing prevalence. Among recognized mechanisms is the oxidative stress that affects melanocytes which are responsible for skin pigmentation. Studies have shown that high concentration of hydrogen peroxide, or H2O2, induces apoptotic activities. Few studies have been done with lower doses of H2O2. Using human skin melanocytes, we investigated the effect of moderate concentration of H2O2 on melanocyte dendrites. Confocal data show that H2O2 at 250 µM induces loss of dendrites, as indicated by cytoskeletal proteins. α-melanocyte stimulating hormone or α-MSH pretreatment protects against H2O2-induced loss of dendrites, while α-MSH alone enhances dendrites. PI3K/AKT inhibitor LY294002 and mTORC1 inhibitor Rapamycin inhibit α-MSH-induced dendrites. In this study, we also investigated the effect of TNFα on cultured human skin melanocytes, since TNFα plays important roles in vitiligo. Confocal data demonstrate that TNFα induces NFκB activation. Western blot analysis shows that TNFα induces IκB phosphorylation and degradation. Interestingly, α-MSH does not have any effect of TNFα-induced IκB degradation and NF-κB activation. α-MSH, however, activates mTORC1 pathway. TNFα induces p38 but not AMPKα activation. Collectively, our data suggest that modulation of mTOR and NF-κB pathways may be a novel approach for better clinical management of vitiligo.

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Section: Discussionmentioning

confidence: 99%

Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

Wan

Lin²,

Zhang

et al. 2017

Int. J. Biol. Sci.

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“…Function The precise function of SLC24A5 has not been elucidated till date. However, the potential functions include: (a) transporting 1 Ca2+ and 1 K+ to the melanosome in exchange for 4 cytoplasmic Na+ [Lamason RL et al, 2005]; (b) Influencing natural variation in skin pigmentation via a novel, unknown mechanism affecting cellular sterol levels [Wilson S et al, 2013] …”

Section: Tyrp1 (Tyrosinase-related Protein 1)mentioning

confidence: 99%

Oculocutaneous Albinism

Ray¹,

Sengupta²,

Ganguly³

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…Gene microarray analysis on siRNA NCKX5 treated normal human melanocytes also showed a loss of MCR1 and altered expression of a number of cholesterol homeostatic genes [21]. Together this data indicates NCKX5 is involved in early melanosome formation.…”

Section: Introductionmentioning

confidence: 96%

A functional approach to understanding the role of NCKX5 in Xenopus pigmentation

et al. 2017

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NCKX5 is an ion exchanger expressed mostly in pigment cells; however, the functional role for this protein in melanogenesis is not clear. A variant allele of SLC24A5, the gene encoding NCKX5, has been shown to correlate with lighter skin pigmentation in humans, indicating a key role for SLC24A5 in determining human skin colour. SLC24A5 expression has been found to be elevated in melanoma. Knockdown analyses have shown SLC24A5 to be important for pigmentation, but to date the function of this ion exchanger in melanogenesis has not been fully established. Our data suggest NCKX5 may have an alternative activity that is key to its role in the regulation of pigmentation. Here Xenopus laevis is employed as an in vivo model system to further investigate the function of NCKX5 in pigmentation. SLC24A5 is expressed in the melanophores as they differentiate from the neural crest and develop in the RPE of the eye. Morpholino knockdown and rescue experiments were designed to elucidate key residues and regions of the NCKX5 protein. Unilateral morpholino injection at the 2 cell stage resulted in a reduction of pigmentation in the eye and epidermis of one lateral side of the tadpole. Xenopus and human SLC24A5 can rescue the morpholino effects. Further rescue experiments including the use of ion exchange inactive SLC24A5 constructs raise the possibility that full ion exchanger function of NCKX5 may not be required for rescue of pigmentation.

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NCKX5, a Natural Regulator of Human Skin Colour Variation, Regulates the Expression of Key Pigment Genes MC1R and Alpha-MSH and Alters Cholesterol Homeostasis in Normal Human Melanocytes

Cited by 18 publications

References 47 publications

Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

Oculocutaneous Albinism

A functional approach to understanding the role of NCKX5 in Xenopus pigmentation

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