GSK3β inhibition promotes melanogenesis in mouse B16 melanoma cells and normal human melanocytes

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Abstract

Glycogen synthase kinase 3β (GSK3β) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and the insulin response. GSK3β also plays a key role in the Wnt/β-catenin pathway. The master regulator of the pigmentation microphthalmia-associated transcription factor (MITF) is a target for the Wnt pathway, however, to date, the regulatory role of GSK3β in the control of melanogenesis has not been elucidated. In this study, we evaluated the effect of inhibiting GSK3β activity on the regulation of melanocyte differentiation. Exposure of the murine melanoma cell line B16 and normal human melanocytes to GSK3β specific inhibitors (SB216763, SB415286, BIO, and LiCl) resulted in a dose-dependent accumulation of β-catenin. This is associated with the induction of melanocyte differentiation-associated markers such as melanin synthesis, tyrosinase activity, and expression of tyrosinase and the microphthalmia-associated transcription factor. Attenuation of GSK3β activity has an inhibitory effect on cell growth, and this was accompanied by morphological changes. Moreover, treatment of B16 cells with a siRNA targeted against β-catenin completely abolished the promelanogenic effect of GSK3β inhibition, however, the overexpression of a constitutively active mutant form of β-catenin (pCS2β-cat-mut) only slightly increased the degree of pigmentation. These results demonstrated that GSK3β is implicated in the regulation of melanogenesis and that pharmacological inhibition of its activity could increase melanin synthesis through mechanisms probably not restricted to Wnt/β-catenin pathway activation.

Original languageEnglish
Pages (from-to)1750-1761
Number of pages12
JournalCellular Signalling
Volume20
Issue number10
DOIs
Publication statusPublished - Oct 2008

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Glycogen Synthase Kinase 3
Experimental Melanomas
Melanocytes
Catenins
Wnt Signaling Pathway
Microphthalmia-Associated Transcription Factor
Monophenol Monooxygenase
Melanins
Pigmentation
Differentiation Antigens
Small Interfering RNA
Embryonic Development
Cell Differentiation
Melanoma
Cats
Pharmacology
Insulin
Apoptosis
Cell Line

Keywords

  • β-catenin
  • Glycogen synthase kinase 3β
  • Melanocytes
  • Melanogenesis
  • Microphthalmia-associated transcription factor
  • Tyrosinase

ASJC Scopus subject areas

  • Cell Biology

Cite this

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title = "GSK3β inhibition promotes melanogenesis in mouse B16 melanoma cells and normal human melanocytes",
abstract = "Glycogen synthase kinase 3β (GSK3β) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and the insulin response. GSK3β also plays a key role in the Wnt/β-catenin pathway. The master regulator of the pigmentation microphthalmia-associated transcription factor (MITF) is a target for the Wnt pathway, however, to date, the regulatory role of GSK3β in the control of melanogenesis has not been elucidated. In this study, we evaluated the effect of inhibiting GSK3β activity on the regulation of melanocyte differentiation. Exposure of the murine melanoma cell line B16 and normal human melanocytes to GSK3β specific inhibitors (SB216763, SB415286, BIO, and LiCl) resulted in a dose-dependent accumulation of β-catenin. This is associated with the induction of melanocyte differentiation-associated markers such as melanin synthesis, tyrosinase activity, and expression of tyrosinase and the microphthalmia-associated transcription factor. Attenuation of GSK3β activity has an inhibitory effect on cell growth, and this was accompanied by morphological changes. Moreover, treatment of B16 cells with a siRNA targeted against β-catenin completely abolished the promelanogenic effect of GSK3β inhibition, however, the overexpression of a constitutively active mutant form of β-catenin (pCS2β-cat-mut) only slightly increased the degree of pigmentation. These results demonstrated that GSK3β is implicated in the regulation of melanogenesis and that pharmacological inhibition of its activity could increase melanin synthesis through mechanisms probably not restricted to Wnt/β-catenin pathway activation.",
keywords = "β-catenin, Glycogen synthase kinase 3β, Melanocytes, Melanogenesis, Microphthalmia-associated transcription factor, Tyrosinase",
author = "Barbara Bellei and Enrica Flori and Enzo Izzo and Vittoria Maresca and Mauro Picardo",
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T1 - GSK3β inhibition promotes melanogenesis in mouse B16 melanoma cells and normal human melanocytes

AU - Bellei, Barbara

AU - Flori, Enrica

AU - Izzo, Enzo

AU - Maresca, Vittoria

AU - Picardo, Mauro

PY - 2008/10

Y1 - 2008/10

N2 - Glycogen synthase kinase 3β (GSK3β) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and the insulin response. GSK3β also plays a key role in the Wnt/β-catenin pathway. The master regulator of the pigmentation microphthalmia-associated transcription factor (MITF) is a target for the Wnt pathway, however, to date, the regulatory role of GSK3β in the control of melanogenesis has not been elucidated. In this study, we evaluated the effect of inhibiting GSK3β activity on the regulation of melanocyte differentiation. Exposure of the murine melanoma cell line B16 and normal human melanocytes to GSK3β specific inhibitors (SB216763, SB415286, BIO, and LiCl) resulted in a dose-dependent accumulation of β-catenin. This is associated with the induction of melanocyte differentiation-associated markers such as melanin synthesis, tyrosinase activity, and expression of tyrosinase and the microphthalmia-associated transcription factor. Attenuation of GSK3β activity has an inhibitory effect on cell growth, and this was accompanied by morphological changes. Moreover, treatment of B16 cells with a siRNA targeted against β-catenin completely abolished the promelanogenic effect of GSK3β inhibition, however, the overexpression of a constitutively active mutant form of β-catenin (pCS2β-cat-mut) only slightly increased the degree of pigmentation. These results demonstrated that GSK3β is implicated in the regulation of melanogenesis and that pharmacological inhibition of its activity could increase melanin synthesis through mechanisms probably not restricted to Wnt/β-catenin pathway activation.

AB - Glycogen synthase kinase 3β (GSK3β) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and the insulin response. GSK3β also plays a key role in the Wnt/β-catenin pathway. The master regulator of the pigmentation microphthalmia-associated transcription factor (MITF) is a target for the Wnt pathway, however, to date, the regulatory role of GSK3β in the control of melanogenesis has not been elucidated. In this study, we evaluated the effect of inhibiting GSK3β activity on the regulation of melanocyte differentiation. Exposure of the murine melanoma cell line B16 and normal human melanocytes to GSK3β specific inhibitors (SB216763, SB415286, BIO, and LiCl) resulted in a dose-dependent accumulation of β-catenin. This is associated with the induction of melanocyte differentiation-associated markers such as melanin synthesis, tyrosinase activity, and expression of tyrosinase and the microphthalmia-associated transcription factor. Attenuation of GSK3β activity has an inhibitory effect on cell growth, and this was accompanied by morphological changes. Moreover, treatment of B16 cells with a siRNA targeted against β-catenin completely abolished the promelanogenic effect of GSK3β inhibition, however, the overexpression of a constitutively active mutant form of β-catenin (pCS2β-cat-mut) only slightly increased the degree of pigmentation. These results demonstrated that GSK3β is implicated in the regulation of melanogenesis and that pharmacological inhibition of its activity could increase melanin synthesis through mechanisms probably not restricted to Wnt/β-catenin pathway activation.

KW - β-catenin

KW - Glycogen synthase kinase 3β

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KW - Melanogenesis

KW - Microphthalmia-associated transcription factor

KW - Tyrosinase

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